10.1007/s11060-009-0073-4</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/s11060-009-0073-4</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of stereotactic = radiosurgery in=20 the management of patients with newly diagnosed brain metastases: a = systematic=20 review and evidence-based clinical practice guideline </DIV> <P class=3DAuthorGroup>Mark E. Linskey<SUP>1</SUP>,=20 David W. Andrews<SUP>2</SUP>, = Anthony L. Asher<SUP>3</SUP>,=20 Stuart H. Burri<SUP>4</SUP>, = Douglas Kondziolka<SUP>5</SUP>,=20 Paula D. Robinson<SUP>6</SUP>, = Mario Ammirati<SUP>7</SUP>,=20 Charles S. Cobbs<SUP>8</SUP>, = Laurie E. Gaspar<SUP>9</SUP>,=20 Jay S. Loeffler<SUP>10</SUP>, = Michael McDermott<SUP>11</SUP>,=20 Minesh P. Mehta<SUP>12</SUP>, 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 Steven N. Kalkanis<SUP>13 <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/7w84227x88442213/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California-Irvine Medical Center, Orange, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </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=3DAff3></A>(3) </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=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 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=3DAff6></A>(6) </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=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>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=3DAff9></A>(9) </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=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 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=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, Evanston, 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> <P><A name=3DContactOfAuthor18></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/7w84227x88442213/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></TD></T= R></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 stereotactic = radiosurgery (SRS)=20 compared with other treatment modalities?=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 newly = diagnosed solid=20 brain metastases amenable to SRS; lesions amenable to SRS are typically = defined=20 as measuring less than 3 cm in maximum diameter and producing = minimal (less=20 than 1 cm of midline shift) mass effect. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>SRS plus WBRT vs. WBRT alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 1</I> Single-dose SRS along with WBRT leads to=20 significantly longer patient survival compared with WBRT alone for = patients with=20 single metastatic brain tumors who have a KPS ≥ 70. = </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Single-dose SRS along with WBRT is = superior in=20 terms of local tumor control and maintaining functional status when = compared to=20 WBRT alone for patients with 1=964 metastatic brain tumors who have a=20 KPS ≥ 70. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Single-dose SRS along with WBRT may lead = to=20 significantly longer patient survival than WBRT alone for patients with = 2=963=20 metastatic brain tumors. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 4</I> There is class III evidence demonstrating = that=20 single-dose SRS along with WBRT is superior to WBRT alone for improving = patient=20 survival for patients with single or multiple brain metastases and a=20 KPS < 70. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>SRS plus WBRT vs. SRS alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Single-dose SRS alone may provide an = equivalent=20 survival advantage for patients with brain metastases compared with=20 WBRT + single-dose SRS. There is conflicting class I and II = evidence=20 regarding the risk of both local and distant recurrence when SRS is used = in=20 isolation, and class I evidence demonstrates a lower risk of distant = recurrence=20 with WBRT; thus, regular careful surveillance is warranted for patients = treated=20 with SRS alone in order to provide early identification of local and = distant=20 recurrences so that salvage therapy can be initiated at the soonest = possible=20 time. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical Resection plus WBRT vs.=20 SRS</I></B> <B><I>=B1</I></B> <B><I>WBRT</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Surgical resection plus WBRT, vs. SRS = plus WBRT,=20 both represent effective treatment strategies, resulting in relatively = equal=20 survival rates. SRS has not been assessed from an evidence-based = standpoint for=20 larger lesions (>3 cm) or for those causing significant mass = effect=20 (>1 cm midline shift). Level 3: Underpowered class I evidence = along with=20 the preponderance of conflicting class II evidence suggests that SRS = alone may=20 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""><B><I>SRS alone vs. WBRT alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> While both single-dose SRS and WBRT are = effective=20 for treating patients with brain metastases, single-dose SRS alone = appears to be=20 superior to WBRT alone for patients with up to three metastatic brain = tumors in=20 terms of patient survival advantage. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Stereotactic radiosurgery - Surgical=20 resection - 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 with cancer will = develop brain=20 metastases. This number is increasing as advances extend cancer patient = survival=20 leading to increasing risk-years for brain metastasis development. The = precise=20 incidence and epidemiology of metastatic brain tumors is poorly studied = and=20 understood, however, it is estimated that approximately 1.4 million = Americans=20 are diagnosed with cancer every year [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/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/7w84227x88442213/fulltext.htm= l#CR2">2</A></CITE>].=20 Solid brain tumors represent 90=9695% of brain metastases with meningeal = involvement accounting for the balance [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR5">5</A></CITE>].=20 Approximately 37=9650% of solid tumor patients present with single brain = metastases while roughly 50=9663% have multiple tumors at initial = presentation=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR7">7</A></CITE>].=20 Given that SRS can treat more than one tumor per session, and that most = tumors=20 are detected while small in size, the percentage of patients that are = potential=20 candidates for SRS is quite large. </P> <P class=3D"">The outcome for patients with brain metastases is = generally poor,=20 with a median survival following WBRT alone of only 3=964 months = regardless=20 of primary tumor histology (small cell lung carcinoma (SCLC) excepted) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR18">18</A></CITE>].=20 Indeed, after WBRT, 50% of patients still succumb to their brain tumor = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR14">14</A></CITE>].=20 These results have driven efforts to improve results by exploring = modalities to=20 improve quality of life through better local control, as well as overall = survival. </P> <P class=3D"">For patients with single accessible brain metastases, = surgical=20 resection followed by post-operative WBRT has been compared to WBRT = alone in=20 three randomized controlled trials (RCT) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR17">17</A></CITE>].The=20 evidence for this combined treatment approach is reviewed in the WBRT = guideline=20 paper of this series by Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR19">19</A></CITE>].=20 </P> <P class=3D"">Outcomes for patients with single solid metastatic brain = tumors=20 amenable to either surgical resection or SRS have been shown to be = roughly=20 equivalent for both local control and overall patient survival [<CITE><A = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR26">26</A></CITE>].=20 Open surgery has the potential for better overall outcomes for lesions=20 >3 cm in diameter in locations amenable to resection with = acceptable=20 risk, and better and/or faster outcomes for smaller lesions causing = symptomatic=20 edema or mass effect. On the other hand, SRS may result in superior = local=20 control rates for radioresistant lesions (e.g., renal cell, melanoma, = etc.), and=20 may allow WBRT to be deferred for subsequent salvage treatment without = adverse=20 sequelae. The evidence for these conclusions is reviewed in the surgical = resection guideline paper in this series by Kalkanis et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR27">27</A></CITE>].=20 SRS has the ability to treat lesions that may not be safely resectable. = </P> <P class=3D"">Patients are generally considered candidates for SRS if = the tumor(s)=20 in question is less than 10 cc in volume (<3 cm average = diameter)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR24">24</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR26">26</A></CITE>].=20 The number of tumors that can be effectively treated with SRS in a given = patient=20 is an area still under study. SRS itself has undergone recent scrutiny = to better=20 define its boundaries. In 2006, the American Society for Therapeutic = Radiology=20 and Oncology (ASTRO), the American Association of Neurological Surgeons = (AANS)=20 and the Congress of Neurological Surgeons (CNS) jointly agreed to define = SRS in=20 a way that includes both traditional single dose SRS, as well as = multi-dose SRS=20 up to five doses (2=965 doses) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">The surgical resection guideline paper in this series = addresses the=20 relative roles of surgical resection plus WBRT vs. SRS + WBRT = for=20 patients with single solid brain metastases. This paper will briefly = summarize=20 those findings but then expand the focus to explore patients with = multiple=20 metastases. This paper will also explore the relative need for WBRT when = SRS is=20 utilized as a sole treatment modality, the relative role of WBRT if SRS = is used=20 to augment surgical resection, as well as the relative role of = multi-dose SRS=20 vs. single dose SRS. </P> <P class=3D"">The overall objectives of this paper are:</P> <P class=3D"">To systematically review the evidence available for the = following=20 treatment comparisons for patients with newly diagnosed brain = metastases. </P> <P class=3D"">WBRT vs. WBRT + SRS</P> <P class=3D"">SRS vs. WBRT +SRS</P> <P class=3D"">WBRT vs. SRS</P> <P class=3D"">SRS + WBRT vs. Resection + WBRT</P> <P class=3D"">SRS vs. Resection + WBRT</P> <P class=3D"">Other Comparisons</P> <P class=3D"">Multi-dose SRS vs. WBRT</P> <P class=3D"">Multi-dose SRS vs. Resection + WBRT or local = radiotherapy=20 (RT)</P> <P class=3D"">Resection + WBRT vs. = Resection + SRS</P> <P class=3D"">Single dose SRS =B1 WBRT vs. Multi-dose=20 SRS + WBRT</P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, Cochrane = Database of=20 Abstracts of Reviews of Effects. A broad search strategy using a = combination of=20 subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR30">30</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 (local=20 RT =3D fractionated radiotherapy localized to the = tumor):=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>WBRT vs. WBRT + SRS</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS vs. WBRT + SRS</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS vs. WBRT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS =B1 WBRT or local RT vs. = Resection =B1 WBRT=20 or local RT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS =B1 Resection vs. = WBRT =B1 Resection</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Single dose SRS =B1 WBRT vs. Multi-dose=20 SRS =B1 WBRT</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with newly diagnosed brain = metastases ≥5=20 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=20 newly diagnosed brain metastases. 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 newly diagnosed brain metastases.=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 was used = to rate=20 the quality of randomized trials [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR31">31</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR32">32</A></CITE>].=20 The quality of comparative studies using non-randomized designs was = evaluated=20 using eight items selected 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 AANS/CNS criteria. These = criteria=20 are provided in the methodology paper to this guideline series. = </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV> <DIV class=3D""><A name=3DSec8></A> <DIV class=3DHeading3>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">Overall 16,966 publications were screened. Fifty-six = publications=20 passed through the title and abstract screening to the full text = screening=20 level. Ultimately, 32 publications (31 primary studies and one companion = paper)=20 met the eligibility criteria. Figure <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Fig1">1</A>=20 outlines the flow of the studies through the review process.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_73_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/7w84227x88442213/MediaObjects/= 11060_2009_73_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> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Whole brain radiotherapy alone versus whole brain=20 radiotherapy plus stereotactic radiosurgery</DIV> <DIV class=3DPara> <DIV class=3D"">Two prospective RCTs (class I evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>]=20 and one retrospective cohort study with historical controls (class III = evidence)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 evaluated WBRT alone vs. WBRT + SRS for the initial management = of=20 patients with solid metastatic brain tumors. One prospective cohort = study (class=20 II evidence) evaluated WBRT alone vs. WBRT + SRS for the = initial=20 management of patients with solid metastatic brain tumors in two arms of = a=20 three-arm study that also evaluated SRS alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>).=20 One retrospective cohort study (class II evidence) evaluated WBRT alone = vs.=20 WBRT + SRS as two of the arms in a four arm study that also = included=20 SRS alone and surgery alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 In all five of these unique studies, only single-dose SRS was evaluated, = and the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Evidence = table=97summary of primary studies </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design </P> <P class=3D"">Evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Population</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/Progression<SUP>c</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=3D7> <P class=3D"">WBRT vs. WBRT + SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Andrews (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 167) </P> <P class=3D"">G2: WBRT + SRS = (<I>n</I> =3D 164) </P></TD> <TD align=3Dleft> <P class=3D"">1=963 BM</P></TD> <TD align=3Dleft> <P class=3D"">Median survival overall:</P> <P class=3D"">G1: 6.5 months</P> <P class=3D"">G2: 5.7 months (Survival curves: log-rank;=20 <I>p</I> =3D NS </P> <P class=3D"">Median survival for single BM pts:</P> <P class=3D"">G1: 4.9 months</P> <P class=3D"">G2: 6.5 months (Survival curves: log-rank;<I>=20 p</I> =3D 0.0393) </P></TD> <TD align=3Dleft> <P class=3D"">Central review assessed 1 yr local control:</P> <P class=3D"">G1: 71%</P> <P class=3D"">G2: 82% (<I>p</I> =3D 0.01) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank;<I> = p</I> =3D 0.0132)=20 </P> <P class=3D"">Overall in brain:Median: NR</P> <P class=3D"">(BR curves: log-rank;<I> p</I> =3D NS) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Kondziolka (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 14) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 13) = </P></TD> <TD align=3Dleft> <P class=3D"">2=964 BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7.5 months</P> <P class=3D"">G2: 11 months (Survival curves: log-rank;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr local failure rate:</P> <P class=3D"">G1: 100%</P> <P class=3D"">G2: 8%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 36 months (LR curves: log-rank;<I>=20 p</I> =3D 0.0016 </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 5 months</P> <P class=3D"">G2: 34 months (Test unclear; = <I>p</I> =3D 0.002)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Sanghavi (2001) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 1200 </P> <P class=3D"">G2: WBRT + SRS = (<I>n</I> =3D 502) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: RPA class I 7.1 months</P> <P class=3D"">G2: RPA class I 16.1 months</P> <P class=3D"">(Greenwood=92s estimates;<I> = p</I> < 0.05) </P> <P class=3D"">G1: RPA class II 4.2 months</P> <P class=3D"">G2: RPA class II 10.3 months</P> <P class=3D"">(Greenwood=92s estimates;<I> = p</I> < 0.05) </P> <P class=3D"">G1: RPA class III 2.3 months</P> <P class=3D"">G2: RPA class III 8.7 months</P> <P class=3D"">(Greenwood=92s estimates;<I> = p</I> < 0.05) </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 colSpan=3D7> <P class=3D"">WBRT vs. SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Datta (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 67) </P> <P class=3D"">G2: SRS =B1 WBRT = (<I>n</I> =3D 53) [12/53=20 (23%) had WBRT prior to SRS] </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 6 months (Survival curves: log-rank;<I>=20 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""> Kocher (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 117) </P> <P class=3D"">G2: WBRT (<I>n</I> =3D 138) </P></TD> <TD align=3Dleft> <P class=3D"">1=963BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: RPA class I 25.4 months</P> <P class=3D"">G2: RPA class I 4.7 months (Test not = reported;<I>=20 p</I> < 0.0001) </P> <P class=3D"">G1: RPA class II 5.9 months</P> <P class=3D"">G2: RPA class II 4.1 months</P> <P class=3D"">(Test not reported;<I> p</I> < 0.04) = </P> <P class=3D"">G1: RPA class III 4.2 months</P> <P class=3D"">G2: RPA class III 2.5 months (Test not = reported;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR by treatment groups</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Lee (2008) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 8) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 7) </P></TD> <TD align=3Dleft> <P class=3D"">BM from epithelial ovarian cancer</P></TD> <TD align=3Dleft> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 29 months (Survival curves; log-rank:<I>=20 p</I> =3D 0.0061) </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""> Rades (2007) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 91) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 95) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7 months</P> <P class=3D"">G2: 13 months (Survival curves: log-rank;<I>=20 p</I> =3D 0.045) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local brain control rate:</P> <P class=3D"">G1: 26%</P> <P class=3D"">G2: 64%</P> <P class=3D"">1 year distant brain control rate:</P> <P class=3D"">G1: 66%</P> <P class=3D"">G2: 61%</P> <P class=3D"">1 yr overall brain control rate:</P> <P class=3D"">G1: 23%</P> <P class=3D"">G2: 49%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: Not reported by treatment group</P> <P class=3D"">(LR curves: log-rank;<I> p</I> < 0.001) = </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">Median: Not reported by treatment group</P> <P class=3D"">(DR curves: log-rank;<I> p</I> =3D NS) = </P> <P class=3D"">Anywhere in brain:</P> <P class=3D"">Median: Not reported by treatment group</P> <P class=3D"">(BR curves: log-rank;<I> p</I> =3D 0.005) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">WBRT vs. SRS vs. WBRT + SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Li (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Prospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 19) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 23) </P> <P class=3D"">G3: SRS + WBRT (<I>n</I> =3D 18) = </P></TD> <TD align=3Dleft> <P class=3D"">Lung cancer BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 5.7 months</P> <P class=3D"">G2: 9.3 months</P> <P class=3D"">G3: 10.6 months</P> <P class=3D"">Survival curves 3 groups: log-rank;<I>=20 p</I> < 0.0001 </P> <P class=3D"">Survival curves G2 vs. G3: log-rank;<I> = p</I> =3D NS=20 </P></TD> <TD align=3Dleft> <P class=3D""># of pts with the following tumor response:</P> <P class=3D"">G1: CR or PR 14/29 (48%)</P> <P class=3D"">no change 11/29 (38%)</P> <P class=3D"">progression 4/29 (14%)</P> <P class=3D"">G2: CR or PR 20/23 (87%)</P> <P class=3D"">no change 3/23 (13%)</P> <P class=3D"">progression 0/23</P> <P class=3D"">G3: CR or PR 16/18 (89%)</P> <P class=3D"">no change 2/18 (11%)</P> <P class=3D"">progression 0/18 (3 groups:<I> = p</I> =3D 0.004) (G2=20 vs. G3:<I> p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 4.0 months</P> <P class=3D"">G2: 6.9 months</P> <P class=3D"">G3: 8.6 months (LR curves of 3 groups: = log-rank;<I>=20 p</I> =3D 0.0000) </P> <P class=3D"">(LR curves G2 vs. G3: log-rank;<I> = p</I> =3D NS) </P> <P class=3D"">At distant sites in brain:</P> <P class=3D"">G1: 4.1 months</P> <P class=3D"">G2: 6.7 months</P> <P class=3D"">G3: 8.6 months (DR curves of 3 groups: = log-rank;<I>=20 p</I> =3D 0.0000) (DR curves G2 vs. G3: log-rank;=20 p =3D 0.0392) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">SRS vs. WBRT + SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Aoyama (2006, 2007) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 67) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 65) = </P></TD> <TD align=3Dleft> <P class=3D"">1=964BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.0 months</P> <P class=3D"">G2: 7.5 months (Survival curves: log-rank;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control rate (by lesion):</P> <P class=3D"">G1: 73%</P> <P class=3D"">G2: 89%</P> <P class=3D"">1 year DR rate:</P> <P class=3D"">G1: 64%</P> <P class=3D"">G2: 42%</P> <P class=3D"">1 yr BR rate:</P> <P class=3D"">G1: 76%</P> <P class=3D"">G2: 47%</P></TD> <TD align=3Dleft> <P class=3D"">At distant brain site:</P> <P class=3D"">Median: NR(DR curves: log-rank;<I> = p</I> =3D 0.003)=20 </P> <P class=3D"">Overall in brain:</P> <P class=3D"">Median: NR (BR curves: log-rank;<I>=20 p</I> < 0.001) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Chidel (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study </P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 78) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 57) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 10.5 months</P> <P class=3D"">G2: 6.4 months (Survival curves: log-rank;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">2 year local control rate:</P> <P class=3D"">G1: 52%</P> <P class=3D"">G2: 80%</P> <P class=3D"">2 year freedom from DR rate: G1: 48%</P> <P class=3D"">G2: 74%</P> <P class=3D"">2 year freedom from BR rate:</P> <P class=3D"">G1: 34%</P> <P class=3D"">G2: 60%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank;<I> = p</I> =3D 0.034)=20 </P> <P class=3D"">At distant brain site:</P> <P class=3D"">Median: NR (DR curves: log-rank;<I> = p</I> =3D NS) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 9.2 months</P> <P class=3D"">G2: 35.1 months (BR curves: log-rank;<I>=20 p</I> =3D 0.027) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Combs (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 10) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 13) = </P> <P class=3D"">G3: SRS for recurrence (<I>n</I> =3D 39) = </P></TD> <TD align=3Dleft> <P class=3D"">Beast cancer BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9 months</P> <P class=3D"">G2: 6 months</P> <P class=3D"">G3:19 months (G1 vs. G2 survival curves = log-rank:<I>=20 p</I> =3D 0.036) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 6.5 months</P> <P class=3D"">G2: 4.0 months</P> <P class=3D"">G3: 9 months (G1 vs. G2 LR curves: log-rank;<I> = p</I> =3D NS) </P> <P class=3D"">At distant brain site:</P> <P class=3D"">G1: 6.5 months</P> <P class=3D"">G2: 4.0 months</P> <P class=3D"">G3: 7 months (G1 vs. G2 DR curves: log-rank;<I> = p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hoffman (2001) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 41) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 19) = </P> <P class=3D"">G3: SRS for recurrent BM (<I>n</I> =3D 53) = </P></TD> <TD align=3Dleft> <P class=3D"">Lung cancer BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 13.9 months</P> <P class=3D"">G2: 14.5 months</P> <P class=3D"">G3: 10.0 months (G1 vs. G2 cox univariate;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR:</P> <P class=3D"">G1: 62%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: 36%</P> <P class=3D"">1 year freedom from DR:</P> <P class=3D"">G1: 33%</P> <P class=3D"">G2: 78%</P> <P class=3D"">G3: 55%</P> <P class=3D"">1 year freedom from BR:</P> <P class=3D"">G1: 13%</P> <P class=3D"">G2: 67%</P> <P class=3D"">G3: 27%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 22.2 months</P> <P class=3D"">G2: Not reached</P> <P class=3D"">G3: 9.2 months (G1 vs. G2 LR curves: log-rank;=20 <I>p</I> =3D NS) </P> <P class=3D"">At distant brain site:</P> <P class=3D"">G1: 8.0 months</P> <P class=3D"">G2: Not reached</P> <P class=3D"">G3: 16.5 months (G1 vs. G2 DR curves: log-rank; = <I>p</I> =3D 0.015) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 6.9 months</P> <P class=3D"">G2: 15.0 months</P> <P class=3D"">G3: 5.8 months (G1 vs. G2 BR curves: log-rank;=20 0.002)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Jawahar (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR43">43</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 43) </P> <P class=3D"">G2: SRS + WBRT (<I>n</I> =3D 18) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR by treatment group (Survival curves: = log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Local tumor control:</P> <P class=3D"">Reported no significant difference between groups = [data:=20 NR]</P> <P class=3D"">Distant tumor recurrence:</P> <P class=3D"">Reported no significant difference between groups = [data:=20 NR]</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Noel (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 34) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 22) = </P> <P class=3D"">G3: SRS for recurrence BM = (<I>n</I> =3D 36) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7 months</P> <P class=3D"">G2: 14 months</P> <P class=3D"">G3: 8 months (G1 vs. G2 survival curves: = log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control rate:</P> <P class=3D"">G1: 78%</P> <P class=3D"">G2: 94%</P> <P class=3D"">G3: 86%</P></TD> <TD align=3Dleft> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 13 months</P> <P class=3D"">G2: 24 months (G1 vs. G2 BR curves: NR)</P> <P class=3D"">G3: Not reached</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Pirzkall (1998) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 158) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 78) = </P></TD> <TD align=3Dleft> <P class=3D"">1=963 BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR by treatment group</P> <P class=3D"">1 year survival rates:</P> <P class=3D"">G1: 19%</P> <P class=3D"">G2: 30% (Survival curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control rate:</P> <P class=3D"">G1: 89%</P> <P class=3D"">G2: 92%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median time: NR (LR curves: log-rank; = <I>p</I> =3D NS)=20 </P> <P class=3D"">At distant brain site:</P> <P class=3D"">G1: 4.3 months</P> <P class=3D"">G2: 5.4 months (<I>p</I> =3D NR) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Sneed (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR46">46</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 62) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 43) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 11.3 months</P> <P class=3D"">G2: 11.1 months (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 13/62 (21%)</P> <P class=3D"">G2: 7/43 (16%)</P> <P class=3D"">At distant brain sites</P> <P class=3D"">G1: 31/62 (50%)</P> <P class=3D"">G2: 12/43 (28%)</P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 36/62 (58%)</P> <P class=3D"">G2: 16/43 (37%)</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 21.0 months</P> <P class=3D"">G2: Not reached (LR curves: log-rank; = <I>p</I> =3D NS)=20 </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: 8.5 months</P> <P class=3D"">G2: 16.8 months (DR curves: log-rank;=20 <I>p</I> =3D 0.03) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 8.3 months</P> <P class=3D"">G2: 15.9 months (BR curves: log-rank;=20 <I>p</I> =3D 0.008) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Sneed (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR47">47</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 268) </P> <P class=3D"">G2: WBRT + SRS = (<I>n</I> =3D 301) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.2 months</P> <P class=3D"">G2: 8.6 months (Univariate Cox; = <I>p</I> =3D NS)=20 </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""> Varlotto (2005) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 40) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 70) = </P></TD> <TD align=3Dleft> <P class=3D"">Pts surviving >1 year after SRS for = BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR by group (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control (by lesion):</P> <P class=3D"">G1: 84%</P> <P class=3D"">G2: 93%</P> <P class=3D"">1 year distant recurrence rates:</P> <P class=3D"">G1: 26%</P> <P class=3D"">G2: 21%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank; = <I>p</I> =3D 0.03)=20 </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">Median: NR (DR curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">SRS vs. Surgery +WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic (2008) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery + WBRT = (<I>n</I> =3D 33) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 31) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9.5 months</P> <P class=3D"">G2: 10.3 months (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from local = recurrence/progression=20 rates:</P> <P class=3D"">G1: 82%</P> <P class=3D"">G2: 97%</P> <P class=3D"">1 year distant recurrence/progression = rates:</P> <P class=3D"">G1: 3%</P> <P class=3D"">G2: 26%</P></TD> <TD align=3Dleft> <P class=3D"">Median time to local recurrence in brain: Not = reported (LR=20 curves: log-rank; <I>p</I> =3D NS) </P> <P class=3D"">Median time to distant recurrence in brain: Not = reported (DR=20 curves: log-rank; <I>p</I> < 0.05) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR58">58</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 35 weeks</P> <P class=3D"">G2: 68 weeks (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR rate:</P> <P class=3D"">G1: 83%</P> <P class=3D"">G2: 75%</P> <P class=3D"">1 year 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 (LR curves: log-rank;=20 <I>p</I> =3D NS) </P> <P class=3D"">At distant site: NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rades (2007) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 94) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 112)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P> <P class=3D"">1 year survival rate:</P> <P class=3D"">G1: 54%</P> <P class=3D"">G2: 38% (Survival curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR rate:</P> <P class=3D"">G1: 64%</P> <P class=3D"">G2: 56%</P> <P class=3D"">1 year freedom from BR rate:</P> <P class=3D"">G1: 49%</P> <P class=3D"">G2: 44%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">Median: NR (BR curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">SRS + WBRT vs. Surgery +WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bindal (1996) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1:=20 Surgery =B1 WBRT<SUP>a</SUP>(n =3D 62)[matched = to G2] </P> <P class=3D"">G2: SRS =B1 WBRT<SUP>a</SUP> = (<I>n</I> =3D 31)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 16.4 months</P> <P class=3D"">G2: 7.5 months (Survival curves:log-rank;=20 <I>p</I> =3D 0.0018) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR rate:</P> <P class=3D"">G2 poorer than G1 [Data: NR]</P> <P class=3D"">1 year 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 (LR curves: log-rank;=20 <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 (DR curves: log-rank;=20 <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Garell (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8 months</P> <P class=3D"">G2: 12.5 months (Survival curves:log-rank;=20 <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""> O=92Neill (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery<SUP>a</SUP> =B1 WBRT=20 (<I>n</I> =3D 74) </P> <P class=3D"">G2: SRS<SUP>a</SUP> =B1 WBRT = (<I>n</I> =3D 23)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P> <P class=3D"">1 year survival rate:</P> <P class=3D"">G1: 62%</P> <P class=3D"">G2: 56% (Survival curves: log-rank; = <I>p</I> =3D NS)=20 </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 (<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> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schoggl (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9 months</P> <P class=3D"">G2: 12 months (Survival curves: test = unclear<SUP>b</SUP>;=20 <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 (LR curves: test = unclear<SUP>b</SUP>=20 <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 (DR curves: test = unclear<SUP>b</SUP>=20 <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Other</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> De Salles (1993) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR62">62</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS =B1 WBRT = (<I>n</I> =3D 19) </P> <P class=3D"">G2: SFR =B1 WBRT = (<I>n</I> =3D 7) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">Average survival:</P> <P class=3D"">G1: 8 months</P> <P class=3D"">G2: 7 months (<I>p</I>-value: NR) </P></TD> <TD align=3Dleft> <P class=3D"">At distant sites in brain:</P> <P class=3D"">G1: 4/19 (21%)</P> <P class=3D"">G2: NR</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ikushima (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR64">64</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1 : SFR (<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) = [RT =3D WBRT or=20 local] </P></TD> <TD align=3Dleft> <P class=3D"">RCC BM</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 (Univariate = analysis<SUP>d</SUP>:G1 vs.=20 G2 + G3: <I>p</I> =3D 0.05) </P></TD> <TD align=3Dleft> <P class=3D"">1 year 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 (LR curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Lindvall (2005) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR63">63</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: SFR (<I>n</I> =3D 47) </P> <P class=3D"">G2: WBRT + SRS or SFR = (<I>n</I> =3D 14)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 5.0 months</P> <P class=3D"">G2: 5.0 months(Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Local response (by lesion) in the pts with available = data:</P> <P class=3D"">G1: stable 37/44 (84%) progression 7/44 (16%)</P> <P class=3D"">G2: stable 11/11 (100%) progression 0/11=20 (<I>p</I> =3D NS) </P> <P class=3D""># of pts with recurrence at distant sites:</P> <P class=3D"">G1: 8/32 (25%)</P> <P class=3D"">G2: 0/11 (<I>p</I> =3D 0.0005) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Serizawa (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR61">61</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT =B1 surgical resection=20 (<I>n</I> =3D 34) </P> <P class=3D"">G2: SRS =B1 surgical resection=20 (<I>n</I> =3D 62) </P></TD> <TD align=3Dleft> <P class=3D"">NSCLC BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 199 days</P> <P class=3D"">G2: 377 days (Survival curves: log-rank:=20 <I>p</I> =3D 0.0158) </P></TD> <TD align=3Dleft> <P class=3D"">1 year tumor control rates:</P> <P class=3D"">G1: NR</P> <P class=3D"">G2: 94.8%</P></TD> <TD align=3Dleft> <P class=3D"">At distant sites in brain:</P> <P class=3D"">G1: 539 days</P> <P class=3D"">G2: 422 days (DR curves: log-rank;=20 <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shinoura (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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)=20 [RT =3D WBRT or local] </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.2 months</P> <P class=3D"">G2: 34.4 months (Survival curves: log-rank;=20 <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%) (<I>p</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">Mean time to recurrence at original site:</P> <P class=3D"">G1: 7.2 months</P> <P class=3D"">G2: 25 months (LR curves: log-rank;=20 <I>p</I> =3D 0.0199) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Wang (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 43.0 weeks</P> <P class=3D"">G2: 37.0 weeks</P> <P class=3D"">G3: 67.0 weeks</P> <P class=3D"">G4: 91.0 weeks (Survival curves: log-rank;=20 <I>p</I> < 0.00001) </P></TD> <TD align=3Dleft> <P class=3D"">Local tumor control at 1 month:</P> <P class=3D"">G1: 89%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: 93%</P> <P class=3D"">G4: 96% (<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>BM</I> Brain metastases, <I>BR</I> Brain = recurrence=20 (local + distant), <I>CR</I> Complete response,=20 <I>DR</I> Distant recurrence in brain,<I> G1</I> Group 1,=20 <I>G2</I> Group 2, <I>G3</I> Group 3, <I>G4</I> Group 4,=20 <I>LR</I> Local recurrence at original site in brain,=20 <I>NSCLC</I> Non-small cell lung cancer, <I>NR</I> Not = reported,=20 <I>NS</I> Not significant, <I>PR</I> Partial response,=20 <I>Pts</I> Patients, <I>RCC</I> Renal cell carcinoma,=20 <I>RCT</I> Randomized control trial, <I>RPA</I> Recursive = partitioning=20 analysis, <I>RT</I> Radiotherapy, <I>SFR</I> Stereotactic = fractionated=20 radiotherapy, <I>SRS</I> Stereotactic radiosurgery,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>WBRT use similar at baseline in both groups=20 </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>b</SUP> Either log-rank or Wilcoxon test = </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>c</SUP> Number of pts with recurrence/progression = of brain=20 metastases, unless otherwise specified </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>d</SUP> Univariate analysis using Cox proportional = hazard=20 model </DIV></DIV></DIV></DIV></DIV> <P class=3D"">The first RCT is a Radiation Therapy Oncology Group (RTOG) = multi-center trial led by Andrews et al., published in 2004 = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 The trial randomized adults with a Karnofsky performance status=20 (KPS) ≥ 70 with 1=963 solid brain metastases with a = maximum diameter of=20 4 cm for the largest and ≤3 cm for the remainder. = Patients were=20 stratified by number of metastases and extent of extra-cranial disease. = WBRT and=20 SRS doses were standard. Overall follow-up was a median of = 12 months.=20 Patient groups were well matched for sex, age (19=9690 years), = histology,=20 KPS, and mini-mental status exam (MMSE) score. There were 164 patients = in the=20 WBRT + SRS arm (of which 31/164 (19%) did not receive their = planned=20 SRS) and 167 patients in the WBRT alone arm (of which 28/167 (17%) = received=20 salvage SRS). The primary endpoint was median survival. Secondary = endpoints=20 included tumor control at 1 year, KPS and MMSE at 6 months and = cause=20 of death (neurologic vs. non-neurologic). This trial can be criticized = for a=20 large bilateral crossover rate in an intent-to-treat model, no follow-up = neuroimaging review on 43% of patients, and inclusion of tumors = >3 cm=20 diameter which are known to be less favorable for SRS but were included = in the=20 original RTOG 90-05 trial and were included for that reason (refer to = the=20 surgical resection guideline paper by Kalkanis et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR27">27</A></CITE>].=20 Nevertheless, this trial demonstrated significantly better survival for = patients=20 with single metastatic tumors (<I>p</I> =3D 0.01), superior = local=20 control for patients with 1=963 metastatic brain tumors=20 (<I>p</I> =3D 0.01), and improved KPS for patients with 1=963 = metastatic=20 brain tumors in the WBRT + SRS arm. The last two conclusions = were=20 secondary endpoints assessed with post hoc analysis and thus, are not as = strong=20 as the single tumor survival conclusion. There was no significant = difference=20 between groups in median survival for patients with 2=963 brain tumors, = MMSE at=20 6 months, incidence of neurologic cause of death, or adverse = therapeutic=20 events [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 However, because of the large follow-up loss in this study, no = conclusion can be=20 assured. </P> <P class=3D"">The second RCT is a single institution study from the = University of=20 Pittsburgh led by Kondziolka et al., published in 1999 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>].=20 The trial randomized adults with a KPS ≥ 70 with 2=964 = solid metastatic=20 brain tumors, each ≤2.5 cm in mean diameter. WBRT and SRS = doses were=20 standard. Overall follow-up was not reported. Patient groups were well = matched=20 for sex, age (33=9677 years), histology, number of brain tumors, = KPS score,=20 and extent of systemic disease. There were 14 patients in the WBRT arm = and 13 in=20 the WBRT + SRS arm. All patients completed the treatment in = their=20 intent-to-treat arm. Since the primary endpoint was imaging-defined = local=20 control, no patient received salvage SRS until they were censored for = analysis.=20 Secondary endpoints included median survival, and time to = recurrence/progression=20 at the original tumor sites. The study was stopped at the 60% accrual = point due=20 to an overwhelmingly positive tumor control difference at interim = analysis. This=20 trial demonstrated significantly better local control rates measured in = terms of=20 local failure at 1 year (8 vs. 100%) and median time to=20 recurrence/progression at original site (36 vs. 6 months) for = patients in=20 the WBRT + SRS arm. Since the study was stopped at 60% = accrual, its=20 statistical power to assess differences in median survival was limited. = Despite=20 a large trend of 11 vs. 7.5 months favoring WBRT + SRS, = this=20 result did not achieve statistical significance due to the relatively = low number=20 of patients. Functional performance outcome, cause of death, and = incidence of=20 adverse events were not reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>].=20 </P> <P class=3D"">In the three arm prospective cohort study by Li = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 recruitment was restricted to patients with both small cell- and = non-small-cell=20 lung cancer (NSCLC) and single brain metastases ≤4.5 cm = diameter in adults=20 with a KPS ≥ 60, two of the three arms were WBRT=20 (<I>n</I> =3D 19) vs. WBRT + SRS = (<I>n</I> =3D 18).=20 Groups were similar in terms of sex, age, histology, extent of = extracranial=20 disease, and KPS score. WBRT doses and SRS doses were standard. The = median=20 survival advantage for WBRT + SRS was highly significant=20 (<I>p</I> < 0.0001) as was the advantage for local tumor = control=20 (<I>p</I> =3D 0.004) and median time to progression for the = treated=20 tumor (<I>p</I> < 0.00001). </P> <P class=3D"">The four arm retrospective cohort study by Wang = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 evaluated adult patients with 1=966 metastases of varying histologies, = each=20 <4 cm in diameter, and a KPS of 40=9690; two of the four arms = were WBRT=20 alone (<I>n</I> =3D 120) vs. WBRT + SRS=20 (<I>n</I> =3D 83). Groups were similar in terms of sex and = age. Primary=20 histology, KPS score, and extent of systemic disease were not reported = by=20 treatment group. The WBRT + SRS had significantly more = patients with=20 multiple brain tumors (50/83) than the WBRT alone arm (34/120). WBRT = doses and=20 SRS doses were standard. While 1 month local tumor control rates = were=20 similar between groups (95.6 vs. 88.3%), median survival significantly = favored=20 the WBRT + SRS group (91 vs. 37 weeks). </P> <P class=3D"">Sanghavi et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 performed a large retrospective cohort trial = (<I>n</I> =3D 502) of=20 patients with varying histologies with historical controls based on = recursive=20 partitioning analysis (RPA) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR37">37</A></CITE>]=20 of a database of patients from RTOG trials = (<I>n</I> =3D 1,200) where=20 patients received WBRT alone. Groups were stratified by RPA class. = Groups were=20 similar in age, and extent of extracranial disease. The WBRT group had = slightly=20 lower KPS scores, while the WBRT + SRS group had a greater = percentage=20 of radioresistant histologies (e.g., melanoma). They found statistically = significant improvements in survival for patients in all three RPA = classes,=20 suggesting a survival benefit for SRS + WBRT even in patients = with=20 >1 metastatic brain tumor, the presence of systemic disease, and low = KPS=20 score. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy plus stereotactic radiosurgery</DIV> <P class=3D"">One prospective RCT (class I evidence) with a companion = paper=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>],=20 and nine retrospective cohort studies (class II evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 evaluated SRS alone vs. WBRT + SRS for the initial management = of=20 patients with solid metastatic brain tumors. One prospective cohort = study (class=20 II evidence) evaluated SRS alone vs. WBRT + SRS for the = initial=20 management of patients with solid metastatic brain tumors in two arms of = a=20 three-arm study that also evaluated WBRT alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>).=20 One retrospective cohort study (class II evidence) evaluated SRS alone = vs.=20 WBRT + SRS as two of the arms in a four arm study that also = included=20 WBRT alone and surgery alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 In all 12 of these unique studies, only single-dose SRS was evaluated, = and the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">The RCT is a multi-institutional study from Japan led by = Aoyama=20 et al., published in 2006 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>].=20 The trial randomized adults with a KPS ≥ 70 with 1=964 = solid brain=20 metastases with a maximum diameter of ≤3 cm. Follow-up was = 20.7 months=20 for the SRS arm and 30.5 months for the WBRT + SRS arm. = Isolated=20 WBRT and SRS alone doses were standard, however, the SRS dose was = reduced by 30%=20 in the WBRT + SRS arm relative to the SRS alone arm. Patient = groups=20 were similar in terms of sex, age, histology, number of tumors, extent, = and=20 stability of extracranial disease, primary tumor status, KPS score, and = MMSE=20 score. There were 67 patients in the SRS alone arm (of which 2/67 (3%) = did not=20 receive SRS, and 11/67 (16%) received WBRT as a salvage therapy) and 65 = in the=20 WBRT + SRS arm (of which 6/65 (9%) did not receive SRS, 2/65 = (3%) did=20 not receive WBRT, and 10/65 (15%) received additional salvage SRS). The = primary=20 endpoint was median survival. Secondary endpoints included 1 year = tumor=20 control rate, 1 year recurrence rate at untreated sites, neurologic = cause=20 of death, 1 year KPS score, 1 year MMSE score, and adverse = event rate.=20 This trial can be criticized for a large bilateral crossover rate in an=20 intent-to-treat model. Results revealed no significant difference = between study=20 groups for median survival (8.0 vs. 7.5 months), 1 year local = control=20 rate (72.5 vs. 88.7%), neurologic cause of death, 1 year KPS score, = MMSE=20 score, or acute or late neurotoxicity. However, the 1 year chance = of=20 recurrence locally (27.5 vs. 11.3%), at a distant site (63.7 vs. 41.5%), = or=20 anywhere in the brain (76.4 vs. 46.8%) was significantly greater for the = SRS=20 alone arm than the WBRT + SRS arm, as was the chance of = requiring=20 additional salvage therapy in the form of either SRS or WBRT (43.3 vs. = 15.4%).=20 In a second, secondary endpoint analysis publication from the same study = looking=20 at the 70% subset of patients with initial and follow-up MMSE = examinations, and=20 then restricting analysis still further to the 62% of patients with=20 pre-treatment MMSE scores of ≥27 or who improved on follow-up to = MMSE scores=20 ≥27, the addition of up-front WBRT significantly increased the = time to MMSE=20 deterioration, which was often due to distant tumor recurrence [<CITE><A = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>].=20 </P> <P class=3D"">In the three arm prospective cohort study by Li = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 recruitment was restricted to patients with both SCLC and NSCLC, and = single=20 brain metastases ≤4.5 cm diameter in adults with a = KPS ≥ 60; two=20 of the three arms were SRS (<I>n</I> =3D 23) vs. = WBRT + SRS=20 (<I>n</I> =3D 18). Groups were similar in terms of sex, age, = histology,=20 extent of extracranial disease, and KPS score. WBRT doses and SRS doses = were=20 standard. There was no significant difference between the two groups in = terms of=20 median survival (9.3 vs. 10.6 months) or in terms of = recurrence/progression=20 at the treated site. Distant brain recurrence was not assessed. </P> <P class=3D"">Of the 10 retrospective cohort studies addressing this = comparison in=20 patients with both single and multiple brain metastases of varying = histologies,=20 nine are direct comparisons of SRS alone vs. WBRT + SRS = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 and one is a four arm retrospective cohort study with SRS and=20 WBRT + SRS as two of the four comparison arms [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 Of these 10 studies, eight show no significant difference in median = survival=20 between both treatment options with ranges for median survival of=20 7=9613.9 months and 6.4=9614.9 months, respectively [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 One study of patients with breast cancer brain metastases showed = improved median=20 survival of 9 vs. 6 months favoring SRS alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>],=20 and another studying tumors of varying histology showed improved median = survival=20 of 91 vs. 67 weeks favoring WBRT + SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 Of the 10 studies, only one (which studied only patients who had = survived=20 >1 year since treatment) revealed a statistically significant = increase=20 in local recurrence rate or reduced time to local recurrence [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 However, four revealed either increased distant brain or overall brain=20 recurrence rates and/or reduced time to distant brain or overall brain=20 recurrence [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>].=20 On the other hand, the study of patients who had survived = >1 year since=20 treatment suggested that while the median time to local = recurrence/progression=20 was significantly increased with SRS alone, the median time to distant=20 recurrence was not significantly different between the two arms = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy alone</DIV> <P class=3D"">No RCTs were identified that met the eligibility criteria = for this=20 treatment comparison. One prospective cohort study (class II evidence) = evaluated=20 SRS alone vs. WBRT alone for the initial management of patients with = solid=20 metastatic brain tumors in two arms of a three-arm study that also = evaluated=20 WBRT + SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>].=20 There were two retrospective cohort studies with concomitant control = groups=20 (class II evidence) that compared SRS alone vs. WBRT alone = (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>].=20 There were two retrospective cohort studies with historical controls = (class III=20 evidence) that compared SRS alone vs. WBRT alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>].=20 One retrospective cohort study (class II evidence) evaluated SRS alone = vs. WBRT=20 alone as two of the arms in a four arm study that also included=20 WBRT + SRS and surgery alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 In all of these unique studies, only single-dose SRS was evaluated, and = the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">The three arm prospective cohort study by Li et al. = (2000)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 evaluated adult patients with both SCLC and NSCLC, and single brain = metastases=20 ≤4.5 cm diameter in adults with a KPS ≥ 60, = two of the three arms=20 were SRS alone (<I>n</I> =3D 23) vs. WBRT alone=20 (<I>n</I> =3D 19). Groups were similar in terms of sex, age, = histology,=20 extent of extracranial disease, and KPS score. WBRT doses and SRS doses = were=20 standard. The SRS alone arm had significantly longer median survival = (9.3 vs.=20 5.7 months), neuroimaging tumor response (complete or partial = response 87=20 vs. 38%, and progression 0 vs. 14%), and median time to progression (6.9 = vs.=20 4.0 months). Distant brain recurrence was not assessed. </P> <P class=3D"">In the small retrospective cohort study by Lee et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>]=20 recruitment was restricted to patients with 1=9612 non-germ cell = epithelial=20 ovarian cancer brain metastases; 15 patients were treated with either = SRS alone=20 (<I>n</I> =3D 7) or WBRT alone (<I>n</I> =3D 8). = Groups were=20 poorly analyzed in terms of potentially relevant intergroup differences = and SRS=20 and WBRT dosing parameter was not provided. Despite these issues, the = authors=20 reported a significantly improved median survival outcome for the SRS = arm (29=20 vs. 6 months for WBRT alone). </P> <P class=3D"">In the large retrospective cohort study by Rades = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>]=20 186 patients with 1=963 brain metastases of varying histologies = ≤4 cm=20 diameter received either WBRT alone (<I>n</I> =3D 91) or SRS = alone=20 (<I>n</I> =3D 95). Groups were well matched for sex, age, RPA = class,=20 number of metastases, extent of extracranial disease, baseline = functional=20 performance, and histology. Median survival was significantly longer for = the SRS=20 alone group (13 vs. 7 months for WBRT alone). One-year local and = overall=20 brain control rates were likewise significantly better for the SRS alone = arm (64=20 vs. 26% and 49 vs. 23%, respectively). Distant brain control rates were = similar=20 for both groups (66% WBRT alone vs. 61% SRS alone). Toxicity rates were = similar=20 for both groups. </P> <P class=3D"">The four arm retrospective cohort study by Wang = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 evaluated adult patients with one or more brain metastases of varying=20 histologies, each <4 cm in diameter and a KPS > 50. = Two of=20 the four arms were SRS alone (<I>n</I> =3D 130) vs. WBRT alone = (<I>n</I> =3D 120). Groups were similar in terms of sex and = age. Primary=20 histology, KPS score, and extent of systemic disease were not reported = by=20 treatment group. The SRS treatment group had more patients with multiple = brain=20 tumors (50/83) than the WBRT alone arm (34/120). WBRT doses and SRS = doses were=20 standard. While 1 month local tumor control rates were similar = between=20 groups (93.3 vs. 88.3%), median survival significantly favored the SRS = group (67=20 vs. 37 weeks). </P> <P class=3D"">Kocher et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>]=20 performed a retrospective cohort trial of SRS = (<I>n</I> =3D 117)=20 compared against 138 WBRT historic control patients treated = 1=9620 years=20 previously at the same institution for brain metastases patients with = multiple=20 histologies and ≤3 tumors. Groups were similar in terms of sex and = age and were=20 stratified according to RPA classification which accounted for extent of = extra-cranial disease, number of tumors, and functional status [<CITE><A = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR37">37</A></CITE>].=20 The SRS alone arm had more melanoma patients (27 vs. 6%). WBRT and SRS = doses=20 were standard. They reported significantly better results with SRS alone = for RPA=20 class I (25.4 vs. 4.7 months) and RPA class II (5.9 vs. = 4.1 months).=20 Difference in results for RPA class III (4.2 vs. 2.5 months) did = not reach=20 statistical significance. </P> <P class=3D"">Datta et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>]=20 performed a retrospective cohort trial of SRS =B1 WBRT (12/53 = (22.6%)=20 received WBRT) compared against 67 WBRT historic control patients = treated=20 1=963 years previously at the same institution for brain metastases = patients=20 with multiple histologies and <4 tumors each <30 cc in = volume. Groups=20 were similar in terms of sex and age, but differed in terms of lung and = breast=20 cancer histology (67.9 vs. 83.6%). Number of brain tumors, extent of=20 extracranial disease, and baseline performance status were not reported. = WBRT=20 and SRS doses were standard. They reported similar median survival of = only=20 6 months for both groups. </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Stereotactic radiosurgery plus WBRT versus = resection plus=20 WBRT</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There were four retrospective = cohort=20 studies (class II evidence) that evaluated SRS + WBRT vs.=20 resection + WBRT for the initial management of patients with = solid=20 metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 In all four of these unique studies, only single-dose SRS was evaluated, = and the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">Bindal et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>]=20 performed a retrospective cohort trial of 62 patients with single brain=20 metastases <3 cm in diameter treated with = resection =B1 WBRT=20 matched for sex, age, histology, KPS, and extent of disease to 31 = patients=20 undergoing SRS =B1 WBRT. WBRT was used in 66% of patients in = the first=20 arm and 71% of patients in the second. WBRT and SRS doses were standard. = In this=20 study, resection + WBRT achieved significantly longer median = survival=20 (16.4 vs. 7.5 months) and median time to recurrence, as well as=20 significantly lower rates of neurologic death (19 vs. 50%) and adverse = event=20 rates than SRS + WBRT. This study reported significantly lower = median=20 survival rates (only 7.5 months), as well as higher radiation = necrosis=20 rates (12.9%), than have ever been reported by other studies evaluating = single=20 brain metastases treated with SRS + WBRT. Given the poor = compliance=20 with completion of WBRT in both arms, this study warrants retrospective=20 down-grading to a class III evidence level, a study with flawed internal = validity. </P> <P class=3D"">In contrast, Garell et al., (1999) (1=962 tumors each = <3 cm diameter, <I>n</I> =3D 45), O=92Neill = et al., (2003)=20 (single tumors <3.5 cm, <I>n</I> =3D 97), and Schoggl=20 et al., (2000) (single tumors <3 cm diameter,=20 <I>n</I> =3D 133) each reported retrospective cohort studies = of patients=20 with brain metastases with very different results [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 Median survival was not significantly different but favored = SRS + WBRT=20 in two (12.5 vs. 8 months and 12 vs. 9 months, respectively) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>],=20 while 1 year survival was not significantly different but slightly = favored=20 resection + WBRT (62 vs. 56%) in the third [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>].=20 Median time to recurrence, incidence of neurologic death, and incidence = of acute=20 and long term adverse events were similar in both arms for the Mayo = Clinic study=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>].=20 Median time to local recurrence was significantly shorter (3.9 vs.=20 4.9 months) and the incidence of neurologic death was greater (21.8 = vs.=20 12.5%) in the resection + WBRT arm in the University of Vienna = study,=20 while adverse event rates were similar [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 Cause of death and adverse event rates were not reported for the = University of=20 Iowa study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>],=20 median time to recurrence was not reported in either the University of = Iowa or=20 the Mayo Clinic Studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>],=20 and functional performance results were not reported in any of the three = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus resection = plus=20 WBRT</DIV> <P class=3D"">One prospective RCT (class I evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>],=20 and two retrospective cohort studies (class II evidence) evaluated SRS = alone vs.=20 resection + WBRT for the initial management of patients with = solid=20 metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR58">58</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>].=20 One retrospective cohort study (class II evidence) evaluated SRS alone = vs.=20 resection + WBRT or local RT for the initial management of = patients=20 with solid metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 These four unique studies only evaluated single-dose SRS, and the = results cannot=20 be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">Muacevic et al., (2008) performed a multicenter = prospective RCT=20 evaluating patients with single metastatic brain tumors, = ≤3 cm diameter=20 located in an operable site, treated with either SRS alone=20 (<I>n</I> =3D 31) or resection + WBRT=20 (<I>n</I> =3D 33) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>].=20 Groups were similar in terms of sex, age, histology, extent of systemic = disease,=20 and KPS score. WBRT and SRS doses were standard. There was no = significant=20 difference in outcome between the two groups in terms of functional = performance=20 outcome, rate of neurological death, or median survival (9.5 months = surgery + WBRT vs. 10.3 months SRS). However, the study = was=20 stopped early at only 25% accrual and was therefore underpowered to = detect=20 <15% differences in outcome between groups. The SRS patients did = experience=20 an increased number of distant tumor recurrences (25.8 vs. 3%), but = these=20 occurrences did not impact overall outcome when subsequent salvage SRS = was taken=20 into account. The resection + WBRT group did experience a=20 significantly larger number of grade 1 or 2 early and late complications = compared with the SRS group. </P> <P class=3D"">Rades et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>]=20 performed a retrospective cohort study of SRS alone = (<I>n</I> =3D 94)=20 vs. resection + WBRT (<I>n</I> =3D 112), for RPA = class I or II=20 patients with metastatic brain tumors ≤4 cm in diameter. = Groups were=20 similar in terms of sex, age, histology, number of brain tumors, extent = of=20 systemic disease, and KPS score. WBRT and SRS doses were standard. = Despite a=20 trend favoring SRS alone, there was no significant difference in outcome = between=20 groups for 1 year survival (54 vs. 38%). There was no significant=20 difference in outcomes for 1 year local recurrence rate (36 vs. = 44%) or=20 incidence of adverse events. Functional performance and neurologic cause = of=20 death outcomes were not reported. </P> <P class=3D"">Muacevic et al., (1999) performed a retrospective = cohort study=20 of SRS alone (<I>n</I> =3D 56) vs. resection + WBRT=20 (<I>n</I> =3D 52), for patients with single metastatic brain = tumors=20 ≤3.5 cm in diameter and with stable systemic disease = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR58">58</A></CITE>].Groups=20 were similar in terms of sex, age, extent of systemic disease, and KPS = score.=20 The SRS alone group had a slightly higher proportion of patients with = melanoma=20 (28.6 vs. 13.5%). WBRT and SRS doses were standard. Despite a trend = favoring=20 resection + WBRT, there was no significant difference in = outcome=20 between groups for median survival (35 vs. 68 weeks). There was no=20 significant difference in outcomes for 1 year local recurrence rate = (17 vs.=20 25%), median time to recurrence, functional performance score, or = incidence of=20 adverse events. </P> <P class=3D"">Shinoura et al., (2002) performed a retrospective = cohort study=20 of SRS alone (<I>n</I> =3D 52) vs. = resection + either WBRT or=20 local RT (<I>n</I> =3D 46, WBRT vs. local RT ratios not = reported) for=20 patients with one or more metastatic brain tumors <3 cm in = diameter=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 Groups were similar in terms of sex, age and histology, but the SRS = alone group=20 had more patients with multiple tumors (77 vs. 37%). Extent of = extracranial=20 disease and functional status were not reported. WBRT, local RT, and SRS = doses=20 were standard. They reported significantly longer median survival rates = (34.4=20 vs. 8.2 months) as well as longer mean time to recurrence rates (25 = vs.=20 7.2 months) for the resection + RT arm. Cause of death = and=20 incidence of adverse events were not reported. </P></DIV> <DIV class=3D""><A name=3DSec14></A> <DIV class=3DHeading3>Other comparisons</DIV> <P class=3D"">While our study group was interested in evaluating many = more=20 treatment comparisons (including the effectiveness of surgery plus SRS = vs.=20 resection plus WBRT, the effectiveness of substituting 2=965 dose SRS or = fractionated stereotactic radiotherapy (6=969 dose) for single dose SRS, = and the=20 effectiveness of substituting local fractionated radiotherapy for WBRT) = in=20 various paradigm combinations, none of these comparisons yielded more = than one=20 clinical study for analysis, and some none at all. As a result, few = conclusions=20 can be drawn at an evidence-based medicine clinical practice parameter = guideline=20 level. Those few studies where evidence exists are presented here for=20 completeness and interest sake and will be discussed further below in = the=20 section on =93<A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Sec26">Key=20 Issues for Further Investigation</A>=94. </P></DIV> <DIV class=3D""><A name=3DSec15></A> <DIV class=3DHeading3>Resection plus whole brain radiotherapy versus = resection=20 plus stereotactic radiosurgery</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 (class II evidence) that evaluated resection + WBRT or local = RT vs.=20 SRS alone for the initial management of patients with solid metastatic = brain=20 tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR61">61</A></CITE>].=20 In this study, only single-dose SRS was evaluated, and the results = cannot be=20 assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">Serizawa et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR61">61</A></CITE>]=20 performed a retrospective cohort study of resection + WBRT=20 (<I>n</I> =3D 34) vs. resection + SRS=20 (<I>n</I> =3D 62) for NSCLC patients with multiple brain = metastases=20 ≤3 cm in diameter in patients estimated to have at least = 2 months to=20 live. Groups were similar in terms of sex, age, number of brain tumors, = extent=20 of systemic disease, and KPS score. WBRT and SRS doses were standard. = The=20 resection + SRS alone group had significantly longer median = survival=20 (377 vs. 199 days). Unfortunately this result is difficult to = evaluate=20 given that the number of patients in the resection + WBRT arm = that had=20 resection of all tumors vs. resection of only some of the 1=9610 tumors = per=20 patient were not defined. The resection + SRS arm also showed=20 significantly longer neurological survival rates. Local tumor control = rates were=20 not reported. </P></DIV> <DIV class=3D""><A name=3DSec16></A> <DIV class=3DHeading3>Single-dose stereotactic radiosurgery versus = multi-dose=20 stereotactic radiosurgery plus whole brain radiotherapy</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 (class II evidence) that evaluated single-dose SRS alone vs. multi-dose=20 SRS + WBRT for the initial management of patients with solid=20 metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR62">62</A></CITE>].=20 </P> <P class=3D"">De Salles et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR62">62</A></CITE>]=20 performed a retrospective cohort study of SRS alone = (<I>n</I> =3D 19)=20 vs. WBRT + multi-dose SRS (<I>n</I> =3D 7) in = patients with=20 multiple histologies with one or more metastatic brain tumors with = volumes=20 ranging from 0.09 to 51.84 cc (average volume 21.2 cc). Groups = were=20 similar in terms of sex and age, but the SRS alone arm had more melanoma = patients (16 vs. 0%) and had significantly more multiple brain tumor = patients=20 (34 tumors in 19 patients vs. seven tumors in seven patients). WBRT and=20 single-dose SRS doses were standard. The multi-dose SRS regimen was = 6 Gy=20 per dose given in 2=963 doses over 2=963 days. There was no = significant=20 difference in average survival between both arms (8 vs. 7 months); = however,=20 this study was underpowered to detect all but a very large difference.=20 </P></DIV> <DIV class=3D""><A name=3DSec17></A> <DIV class=3DHeading3>Multi-dose stereotactic radiosurgery versus whole = brain=20 radiotherapy plus either single- or multi-dose SRS</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 with historical controls (class III evidence) that evaluated multi-dose = SRS vs.=20 WBRT for the initial management of patients with solid metastatic brain = tumors=20 (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR63">63</A></CITE>].=20 </P> <P class=3D"">Lindvall et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR63">63</A></CITE>]=20 performed a retrospective cohort study of multi-dose SRS alone vs.=20 WBRT + either single- or multi-dose SRS in patients with 1=963 = brain=20 metastases of varying histologies ranging in volume from 0.9 to = 41 cc=20 (median volume 5 cc). Groups were similar in terms of sex, extent = of=20 systemic disease, and KPS score. The multi-dose SRS arm had younger = patients=20 (61.7% ≥ 60 vs. 85.7% ≥ 60), fewer = melanoma patients (4.3=20 vs. 21.4%), fewer RPA class I patients (4.3 vs. 21.4%) and more patients = with=20 multiple brain tumors (23.4 vs. 14.2%). The WBRT dose was standard. The=20 multi-dose SRS regimen was 40 Gy in five 8 Gy doses. The = single- or=20 multi-dose boost regimen after WBRT was given in 1=963 doses of = 6=9612 Gy (mean=20 total dose 17 Gy). There was no significant difference in outcomes = between=20 groups for median survival (5 vs. 5 months) or local progression = (16 vs.=20 0%). There was a significantly larger distant recurrence rate for the = multi-dose=20 SRS alone arm (25 vs. 0%). </P></DIV> <DIV class=3D""><A name=3DSec18></A> <DIV class=3DHeading3>Fractionated stereotactic radiotherapy alone = versus=20 resection with either whole brain radiotherapy or local radiotherapy = versus=20 whole brain radiotherapy or local radiotherapy alone </DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 (class II evidence) that evaluated fractionated stereotactic = radiotherapy (FSR)=20 alone vs. resection plus WBRT or local RT vs. WBRT or local RT alone, = for the=20 initial management of patients with solid metastatic brain tumors = (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR64">64</A></CITE>].=20 </P> <P class=3D"">Ikushima et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR64">64</A></CITE>]=20 performed a three arm retrospective cohort study in patients with 1=963 = renal cell=20 carcinoma brain metastases each ≤3 cm in diameter in adult = patients with an=20 Eastern Cooperative Oncology Group (ECOG) performance status of = ≤2, comparing=20 FSR (<I>n</I> =3D 10) vs. resection + either WBRT or = local RT=20 vs. WBRT or local RT alone. Patients were similar in terms of sex, age, = and=20 extent of extracranial disease. The FSR alone arm had more patients with = single=20 brain tumors, and the WBRT or local RT alone arm had less patients with = multiple=20 brain tumors than the resection + either WBRT or local RT arm = (90 vs.=20 70% and 50 vs. 36%, respectively). The WBRT or local RT alone arm had = more ECOG=20 performance status two patients than either the = resection + either=20 WBRT or local RT, or the FSR alone arm (50 vs. 18 vs. 0%). The WBRT and = local RT=20 doses were standard. The FSR regimen was 42 Gy in seven fractions=20 (6 Gy per fraction) over 2.3 weeks. While 1 year tumor = control=20 rates where similar for the FSR alone and the = resection + either WBRT=20 or local RT arms (89.6 vs. 87.5%), the FSR group had a significantly = longer=20 median survival (25.6 months) than either the = surgery + either=20 WBRT or local RT (18.7 months), or the WBRT or local RT alone arms=20 (4.3 months). </P></DIV></DIV> <DIV class=3D""><A name=3DSec19></A> <HR> <DIV class=3Dheading2>Summary and discussion</DIV> <DIV class=3D""><A name=3DSec20></A> <DIV class=3DHeading3>Whole brain radiotherapy alone versus whole brain=20 radiotherapy plus stereotactic radiosurgery</DIV> <P class=3D"">There is class I evidence from two RCTs with similar = inclusion=20 criteria that single-dose SRS + WBRT provides significantly = superior=20 local tumor control compared with WBRT alone for patients with 1=963 = brain=20 metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>]=20 and evidence from one of the RCTs that this applies in patients with up = to four=20 brain tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>].=20 One of the RCTs also showed improved KPS score results for the = single-dose=20 SRS + WBRT regimen [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 These results were achieved without an increased incidence of adverse=20 therapeutic events [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 While local control was a secondary endpoint, assessed post hoc in one = of the=20 RCTs [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>],=20 it was the primary endpoint in the second [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>],=20 which confirmed the conclusion. Based on the inclusion criteria for both = RCTs, a=20 level 1 recommendation for single-dose SRS + WBRT would only = have=20 external validity for patients with a KPS ≥ 70. </P> <P class=3D"">There is class I evidence from one RCT that single-dose=20 SRS + WBRT provides a significantly superior survival benefit = compared=20 with WBRT alone for patients with single brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 Once again, a level 1 recommendation reflecting a survival advantage in = this=20 setting for single-dose SRS + WBRT would only have external = validity=20 for patients with a KPS ≥ 70. </P> <P class=3D"">Whether or not a survival advantage might also exist for = patients=20 with ≥2 brain metastases remains controversial. Local tumor = control is often=20 assumed to dictate survival in a disease where 50% of patients die a=20 neurological death with WBRT alone. It can be argued that one of the two = RCTs=20 was affected by excessive bilateral cross over (especially in the 2=963 = tumor=20 patient group) confounding the intent-to-treat survival analysis for = patients=20 with 2=963 tumors, while the second RCT, using local control as the = primary=20 endpoint, was stopped at too low a power to statistically prove a = survival=20 advantage in patients with 1=964 brain metastases. Certainly, the one = class II=20 evidence study that includes patients with 1=966 metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 as well as the single class III evidence study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 consistently support a significant survival advantage for single-dose=20 SRS + WBRT in patients with multiple metastatic brain tumors.=20 Nevertheless, a survival advantage for patients with 2=964 tumors has = yet to be=20 proven at the class I evidence level, and at most a qualified level 2=20 recommendation can be supported. </P> <P class=3D"">One class II study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 and one class III study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>],=20 each found a survival advantage for SRS + WBRT vs. WBRT alone = for=20 patients with a KPS < 70, irrespective of brain tumor = number, so=20 long as all tumors were treated. The four arm retrospective cohort study = by Wang=20 et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 included patients with 1=966 brain metastases and KPS scores of 40=9690. = Unfortunately the KPS score distributions were not stratified by = treatment group=20 for comparison purposes. The Sanghavi et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR37">37</A></CITE>]=20 retrospective cohort study compared against the RTOG database and = stratified by=20 RPA classification is a much better designed study, but only rises to = the class=20 III evidence level. At most, the evidence supports a qualified level 3=20 recommendation regarding a survival advantage for SRS + WBRT = over WBRT=20 alone for patients with a KPS < 70. </P></DIV> <DIV class=3D""><A name=3DSec21></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy plus stereotactic radiosurgery</DIV> <P class=3D"">One RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>],=20 one prospective cohort study (class II evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>],=20 and eight of 10 retrospective cohort studies (class II evidence) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 support equivalent survival results for single-dose SRS alone vs.=20 WBRT + single-dose SRS, and one study restricted to breast = cancer=20 suggested a survival advantage for the single-dose SRS alone strategy = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>].=20 Only one retrospective cohort study showed a survival result favoring=20 WBRT + single-dose SRS, and this study was unusual in that it = only=20 included patients who had already survived >1 year since initial = treatment [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 </P> <P class=3D"">Regarding local recurrence risk, the RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>]=20 as well as 1/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 demonstrated that a single-dose SRS alone strategy led to a higher risk = of local=20 recurrence at the treated site compared with = WBRT + single-dose SRS. A=20 third study (second retrospective cohort study) reported an increased=20 1 year local recurrence rate (22 vs. 6%) but did not report = statistical=20 analysis [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>].=20 In contrast, the prospective cohort study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 as well as 6/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR43">43</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR46">46</A></CITE>]=20 showed no significant difference in local recurrence risk at the treated = site=20 between the two treatment strategies. Clearly there exists conflicting = data=20 regarding the risk of local recurrence at the treated site if = single-dose SRS is=20 utilized in isolation. This conflicting evidence suggests that further = study may=20 be needed to define optimal dose prescription and/or dose rate for = isolated SRS=20 as opposed to SRS performed in the setting of an additive WBRT dose. = </P> <P class=3D"">Three class I studies have demonstrated that WBRT lowers = the risk of=20 distant recurrence compared to local tumor therapies (SRS or surgical = resection)=20 used in isolation [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>].=20 There is, however, disagreement among class I and II studies regarding = the risk=20 of distant recurrence outside the treatment volume if single-dose SRS is = used in=20 isolation as opposed to WBRT + single-dose SRS. The RCT = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>],=20 as well as 4/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>],=20 demonstrated a significantly increased risk of either distant brain or = overall=20 brain recurrence when single-dose SRS is utilized in isolation and no = advantage=20 to SRS alone when assessing neurocognitive sequelae from radiation. The=20 prospective cohort study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 as well as 2/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR47">47</A></CITE>]=20 did not assess the distant recurrence rate. Four of 10 retrospective = cohort=20 studies, however, revealed no significant difference in the distant = recurrence=20 rate between the two treatment strategies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR43">43</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR46">46</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 Given the above results, prudence warrants regular careful surveillance = at=20 2=963 month intervals with neuro-imaging if single-dose SRS is = utilized in=20 isolation. </P> <P class=3D"">An area that has not been fully studied to date includes = the=20 potential neuropsychological effects of adding WBRT to a SRS treatment = regimen=20 vs. the potential adverse neurocognitive effects of a potentially = greater risk=20 of recurrence outside the SRS site. Assessing functional status outcomes = using=20 standard functional scores tends to be insensitive to subtle = neurocognitive=20 effects. Even the MMSE is likely to be too crude a measure to assess the = neurocognitive parameters of interest to physicians and patients. Thus, = a=20 careful surveillance imaging strategy, if SRS is utilized in isolation, = should=20 be validated for both efficacy and for preserving neurocognitive = function. While=20 outside the specific search criteria for this chapter, limited evidence = to date=20 suggests that tumor recurrence is also associated with neurocognitive = decline=20 and thus may be taken into consideration when deciding to forego = up-front WBRT.=20 The potential differential neurocognitive consequences between these two = therapeutic choices (SRS alone vs. SRS + WBRT) have not been = well=20 studied and remain uncertain, even if a careful surveillance strategy is = implemented when SRS is used in isolation. </P></DIV> <DIV class=3D""><A name=3DSec22></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy alone</DIV> <P class=3D"">The four class II evidence studies evaluating this = comparison all=20 demonstrated a statistically significant survival advantage for = single-dose SRS=20 alone compared with WBRT alone for patients with either single or = multiple brain=20 tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>].=20 However, one study was confounded by the inclusion of SCLC patients who = are=20 normally excluded from solid metastatic brain tumor analysis, = particularly in a=20 study in which WBRT is not included in one of the arms [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>].=20 A second study included a very small number of patients and was limited = by=20 selective rare histology (epithelial ovarian cancer only), and poor = intergroup=20 comparative analysis [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>].=20 Consistent with these results, one class III evidence study showed a = significant=20 survival advantage for single-dose SRS alone for RPA class I and II, but = not RPA=20 class III patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>].=20 Only one class III evidence study showed similar survival results for = both=20 treatment strategies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>].=20 While different studies evaluated patients with differing numbers of = brain=20 metastases, all studies included patients with up to three metastatic = brain=20 tumors. Given the relative paucity and weakness of the data, and despite = relatively consistent results, only a level 3 recommendation is = warranted.=20 </P></DIV> <DIV class=3D""><A name=3DSec23></A> <DIV class=3DHeading3>Stereotactic radiosurgery plus WBRT versus = resection plus=20 WBRT</DIV> <P class=3D"">Of the four retrospective cohort trials evaluating this = comparison,=20 three demonstrated no significant survival differences between the two=20 strategies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 Of these, two showed a trend favoring single-dose SRS + WBRT = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>]=20 and one a trend favoring resection + WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>].=20 Only one of the studies demonstrated a significant survival advantage = for=20 resection + WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>].=20 This study reported SRS + WBRT results far worse than those = reported=20 by most studies using this strategy, both in terms of per survival = results as=20 well as excessive therapeutic toxicity and had poor enough internal = validity=20 that our writing group favored down-grading it from class II to class = III=20 evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>].=20 As further outlined and discussed in the surgical resection practice = guideline=20 of this series for brain metastases, these results suggest equivalence = in=20 survival results and a level 2 recommendation is consistent between the = two=20 guideline papers. </P></DIV> <DIV class=3D""><A name=3DSec24></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus resection = plus=20 WBRT</DIV> <P class=3D"">One class I evidence study evaluating this comparison = revealed no=20 significant difference in functional performance outcome, neurological = death=20 outcome or median survival for patients with single brain metastases = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>].=20 However, this study was closed prematurely with only 25% patient accrual = for a=20 study originally designed to detect a 15% difference in survival between = the two=20 groups. The revised statistical power calculation based on actual = accrual data=20 was designed to detect a survival difference of 38% or more in favor of = surgery=20 with 80% power (in accordance with a scenario retrospectively described = by=20 Bindal et al. in 1996). The actual sample size was large enough to = reject=20 the Bindal hypothesis concerning the overwhelming impact of surgery and = in fact,=20 revealed no significant difference between the two groups. </P> <P class=3D"">Of the three class II evidence studies evaluating this = comparison,=20 two revealed no significant difference in median survival for patients = with 1=963=20 brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 One suggested a trend favoring single-dose SRS alone for patients with = 1=963=20 tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>],=20 while the other suggested a trend favoring resection + WBRT = for=20 patients with single metastatic tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 The third study demonstrating a significant survival advantage for=20 resection + WBRT or local RT was confounded by poor = comparability=20 among patient treatment arms with the SRS alone arm containing more than = twice=20 the percentage of multiple metastatic brain tumor patients than the=20 resection + RT arm [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 </P> <P class=3D"">While the result for this comparison is one of the most = eagerly=20 anticipated in neuro-oncology, the current power flaws for the only = class I=20 evidence study, as well as the relative paucity, weakness, and = conflicting=20 results among other published evidence at most supports a level 3 = recommendation=20 for SRS in lieu of resection + WBRT. </P></DIV> <DIV class=3D""><A name=3DSec25></A> <DIV class=3DHeading3>Other comparisons</DIV> <DIV class=3DPara> <DIV class=3D"">The absent and/or severely limited evidence (number as = well as=20 quality of studies) so far published in peer review literature does not = yet=20 support any clinical practice parameter guideline recommendations = regarding:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>The effectiveness of resection + single-dose SRS vs.=20 resection + WBRT for patients with one or more solid = brain=20 metastases.</TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>The effectiveness of substituting 2=965 dose SRS, or even 6=969 = dose FSR,=20 for single-dose SRS evaluated in the comparisons above and = reflected in=20 the clinical practice parameter guideline recommendations. = </TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>The effectiveness of substituting local RT for WBRT in the = comparisons=20 above and reflected in the clinical practice parameter guideline=20 recommendations. </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec26></A> <DIV class=3DHeading3>Key issues for further investigation</DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>The potential survival advantage of single-dose = SRS + WBRT=20 for patients with ≥2 metastatic brain tumors <3 cm = in diameter=20 remains controversial and warrants further investigation with a = RCT=20 designed for sufficient statistical power for these patients with = median=20 survival as the primary endpoint. </TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>The potential survival advantage of single-dose = SRS + WBRT=20 for patients with a KPS < 70 warrants further = investigation=20 in the form of a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>The local control advantage of single-dose SRS for patients with = ≥4=20 metastatic brain tumors and a KPS ≥ 70 warrants = further=20 investigation in the form of a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>The optimal dose and/or dose rate for single-dose SRS utilized = in=20 isolation for treating metastatic brain tumors in order to ensure=20 equivalent local recurrence rates compared with current single = dose=20 SRS + WBRT doses warrants further study. </TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>The neurocognitive effects of SRS alone with careful = neuroimaging=20 follow-up leading to potential salvage SRS if recurrence develops, = vs.=20 SRS + WBRT, warrants further study with appropriate = validated=20 neurocognitive instruments and endpoints. </TD></TR> <TR vAlign=3Dtop> <TD>6. </TD> <TD>Based on current evidence classifications, single-dose=20 SRS + WBRT vs. resection + WBRT warrants = investigation=20 in the form of a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>7. </TD> <TD>Single-dose SRS alone vs. resection + WBRT warrants = further=20 investigation in the form of either a prospective cohort study or = a RCT.=20 </TD></TR> <TR vAlign=3Dtop> <TD>8. </TD> <TD>Resection + single-dose SRS vs. = resection + WBRT=20 warrants further investigation in the form of either a prospective = cohort=20 study or a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>9. </TD> <TD>2=965 dose SRS is relatively unproven in any of the comparison = paradigms=20 discussed in this paper. Clinical trials of 2=963 dose SRS vs. = single-dose=20 SRS are needed for all treatment comparisons outlined in this = paper in=20 either the form of prospective cohort studies or RCTs. </TD></TR> <TR vAlign=3Dtop> <TD>10. </TD> <TD>The effectiveness of local RT is relatively unproven compared = with=20 WBRT in any of the comparison paradigms discussed in this paper. = Clinical=20 trials of local RT vs. WBRT are most needed for settings of = limited CNS=20 disease where treatment strategies are designed to maximize local = control=20 (e.g., SRS + local RT vs. SRS + WBRT or=20 resection + local RT vs. resection + WBRT).=20 </TD></TR></TBODY></TABLE></DIV></DIV> <DIV class=3DPara> <DIV class=3D"">The following is a list of major ongoing randomized = trials=20 pertaining to the use of stereotactic radiosurgery that evaluate = treatment=20 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>Randomized trial comparing radiosurgery with vs without whole = brain=20 radiotherapy=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A phase III prospective = randomized=20 trial comparing radiosurgery with versus without whole brain = radiotherapy=20 for 1=963 newly diagnosed brain 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> NCT00548756=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Eric L. Chang, MD, = U.T.M.D.=20 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>2. </TD> <TD>Stereotactic radiation therapy with or without whole-brain = radiation=20 therapy in treating patients with brain metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Phase III randomized trial = of the=20 role of whole brain radiation therapy in addition to radiosurgery = in=20 patients with one to three cerebral 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> NCT00377156=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Paul D. Brown, MD Mayo = Clinic</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Kurt A. Jaeckle, MD Mayo = Clinic</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Richard L. Deming, MD Mercy = Therapeutic=20 Radiology Associates, PC at Mercy Medical Center - Des = Moines</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Elana Farace, PhD Milton S. Hershey = Medical=20 Center</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Bruce Pollock, MD Mayo = Clinic</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Anthony Asher, MD, FACS Carolina = Neurosurgery=20 and Spine Associates</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Fred G. Barker, MD Massachusetts = General=20 Hospital</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Larry Kleinberg, MD Sidney Kimmel = Comprehensive=20 Cancer Center</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Anthony Asher, MD, FACS Carolina = Neurosurgery=20 and Spine Associates</DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States and Canada (38 = locations)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">North Central Cancer Treatment Group</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">National Cancer Institute (NCI)</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">American College of Surgeons</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Eastern Cooperative Oncology Group</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Radiation Therapy Oncology = Group</DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>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>4. </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>5. </TD> <TD>A trial of postoperative whole brain radiation therapy vs. = 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> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Japan Clinical Oncology Group</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Japanese Ministry of Health, Labor and=20 Welfare</DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>6. </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""><B>Principal Investigator:</B> Daniel Roos, = FRANZCR, Royal=20 Adelaide 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>7. </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> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Rolf-Peter Mueller, MD Medizinische = Universitaetsklinik I at=20 the University of Cologne</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Riccardo Soffietti, MD Universita Degli Studi di=20 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 = &=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/s11060-009-0073-4 Date: Thu, 24 Dec 2009 12:50:28 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0013_01CA8497.ABAC14B0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0013_01CA8497.ABAC14B0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/7w84227x88442213/fulltext.html 10.1007/s11060-009-0073-4</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/s11060-009-0073-4</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of stereotactic = radiosurgery in=20 the management of patients with newly diagnosed brain metastases: a = systematic=20 review and evidence-based clinical practice guideline </DIV> <P class=3DAuthorGroup>Mark E. Linskey<SUP>1</SUP>,=20 David W. Andrews<SUP>2</SUP>, = Anthony L. Asher<SUP>3</SUP>,=20 Stuart H. Burri<SUP>4</SUP>, = Douglas Kondziolka<SUP>5</SUP>,=20 Paula D. Robinson<SUP>6</SUP>, = Mario Ammirati<SUP>7</SUP>,=20 Charles S. Cobbs<SUP>8</SUP>, = Laurie E. Gaspar<SUP>9</SUP>,=20 Jay S. Loeffler<SUP>10</SUP>, = Michael McDermott<SUP>11</SUP>,=20 Minesh P. Mehta<SUP>12</SUP>, 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 Steven N. Kalkanis<SUP>13 <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/7w84227x88442213/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California-Irvine Medical Center, Orange, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </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=3DAff3></A>(3) </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=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 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=3DAff6></A>(6) </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=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>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=3DAff9></A>(9) </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=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 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=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, Evanston, 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> <P><A name=3DContactOfAuthor18></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/7w84227x88442213/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></TD></T= R></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 stereotactic = radiosurgery (SRS)=20 compared with other treatment modalities?=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 newly = diagnosed solid=20 brain metastases amenable to SRS; lesions amenable to SRS are typically = defined=20 as measuring less than 3 cm in maximum diameter and producing = minimal (less=20 than 1 cm of midline shift) mass effect. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>SRS plus WBRT vs. WBRT alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 1</I> Single-dose SRS along with WBRT leads to=20 significantly longer patient survival compared with WBRT alone for = patients with=20 single metastatic brain tumors who have a KPS ≥ 70. = </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Single-dose SRS along with WBRT is = superior in=20 terms of local tumor control and maintaining functional status when = compared to=20 WBRT alone for patients with 1=964 metastatic brain tumors who have a=20 KPS ≥ 70. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Single-dose SRS along with WBRT may lead = to=20 significantly longer patient survival than WBRT alone for patients with = 2=963=20 metastatic brain tumors. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 4</I> There is class III evidence demonstrating = that=20 single-dose SRS along with WBRT is superior to WBRT alone for improving = patient=20 survival for patients with single or multiple brain metastases and a=20 KPS < 70. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>SRS plus WBRT vs. SRS alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Single-dose SRS alone may provide an = equivalent=20 survival advantage for patients with brain metastases compared with=20 WBRT + single-dose SRS. There is conflicting class I and II = evidence=20 regarding the risk of both local and distant recurrence when SRS is used = in=20 isolation, and class I evidence demonstrates a lower risk of distant = recurrence=20 with WBRT; thus, regular careful surveillance is warranted for patients = treated=20 with SRS alone in order to provide early identification of local and = distant=20 recurrences so that salvage therapy can be initiated at the soonest = possible=20 time. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Surgical Resection plus WBRT vs.=20 SRS</I></B> <B><I>=B1</I></B> <B><I>WBRT</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Surgical resection plus WBRT, vs. SRS = plus WBRT,=20 both represent effective treatment strategies, resulting in relatively = equal=20 survival rates. SRS has not been assessed from an evidence-based = standpoint for=20 larger lesions (>3 cm) or for those causing significant mass = effect=20 (>1 cm midline shift). Level 3: Underpowered class I evidence = along with=20 the preponderance of conflicting class II evidence suggests that SRS = alone may=20 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""><B><I>SRS alone vs. WBRT alone</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> While both single-dose SRS and WBRT are = effective=20 for treating patients with brain metastases, single-dose SRS alone = appears to be=20 superior to WBRT alone for patients with up to three metastatic brain = tumors in=20 terms of patient survival advantage. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Stereotactic radiosurgery - Surgical=20 resection - 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 with cancer will = develop brain=20 metastases. This number is increasing as advances extend cancer patient = survival=20 leading to increasing risk-years for brain metastasis development. The = precise=20 incidence and epidemiology of metastatic brain tumors is poorly studied = and=20 understood, however, it is estimated that approximately 1.4 million = Americans=20 are diagnosed with cancer every year [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/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/7w84227x88442213/fulltext.htm= l#CR2">2</A></CITE>].=20 Solid brain tumors represent 90=9695% of brain metastases with meningeal = involvement accounting for the balance [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR5">5</A></CITE>].=20 Approximately 37=9650% of solid tumor patients present with single brain = metastases while roughly 50=9663% have multiple tumors at initial = presentation=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR7">7</A></CITE>].=20 Given that SRS can treat more than one tumor per session, and that most = tumors=20 are detected while small in size, the percentage of patients that are = potential=20 candidates for SRS is quite large. </P> <P class=3D"">The outcome for patients with brain metastases is = generally poor,=20 with a median survival following WBRT alone of only 3=964 months = regardless=20 of primary tumor histology (small cell lung carcinoma (SCLC) excepted) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR18">18</A></CITE>].=20 Indeed, after WBRT, 50% of patients still succumb to their brain tumor = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR14">14</A></CITE>].=20 These results have driven efforts to improve results by exploring = modalities to=20 improve quality of life through better local control, as well as overall = survival. </P> <P class=3D"">For patients with single accessible brain metastases, = surgical=20 resection followed by post-operative WBRT has been compared to WBRT = alone in=20 three randomized controlled trials (RCT) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR17">17</A></CITE>].The=20 evidence for this combined treatment approach is reviewed in the WBRT = guideline=20 paper of this series by Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR19">19</A></CITE>].=20 </P> <P class=3D"">Outcomes for patients with single solid metastatic brain = tumors=20 amenable to either surgical resection or SRS have been shown to be = roughly=20 equivalent for both local control and overall patient survival [<CITE><A = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR26">26</A></CITE>].=20 Open surgery has the potential for better overall outcomes for lesions=20 >3 cm in diameter in locations amenable to resection with = acceptable=20 risk, and better and/or faster outcomes for smaller lesions causing = symptomatic=20 edema or mass effect. On the other hand, SRS may result in superior = local=20 control rates for radioresistant lesions (e.g., renal cell, melanoma, = etc.), and=20 may allow WBRT to be deferred for subsequent salvage treatment without = adverse=20 sequelae. The evidence for these conclusions is reviewed in the surgical = resection guideline paper in this series by Kalkanis et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR27">27</A></CITE>].=20 SRS has the ability to treat lesions that may not be safely resectable. = </P> <P class=3D"">Patients are generally considered candidates for SRS if = the tumor(s)=20 in question is less than 10 cc in volume (<3 cm average = diameter)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR24">24</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR26">26</A></CITE>].=20 The number of tumors that can be effectively treated with SRS in a given = patient=20 is an area still under study. SRS itself has undergone recent scrutiny = to better=20 define its boundaries. In 2006, the American Society for Therapeutic = Radiology=20 and Oncology (ASTRO), the American Association of Neurological Surgeons = (AANS)=20 and the Congress of Neurological Surgeons (CNS) jointly agreed to define = SRS in=20 a way that includes both traditional single dose SRS, as well as = multi-dose SRS=20 up to five doses (2=965 doses) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">The surgical resection guideline paper in this series = addresses the=20 relative roles of surgical resection plus WBRT vs. SRS + WBRT = for=20 patients with single solid brain metastases. This paper will briefly = summarize=20 those findings but then expand the focus to explore patients with = multiple=20 metastases. This paper will also explore the relative need for WBRT when = SRS is=20 utilized as a sole treatment modality, the relative role of WBRT if SRS = is used=20 to augment surgical resection, as well as the relative role of = multi-dose SRS=20 vs. single dose SRS. </P> <P class=3D"">The overall objectives of this paper are:</P> <P class=3D"">To systematically review the evidence available for the = following=20 treatment comparisons for patients with newly diagnosed brain = metastases. </P> <P class=3D"">WBRT vs. WBRT + SRS</P> <P class=3D"">SRS vs. WBRT +SRS</P> <P class=3D"">WBRT vs. SRS</P> <P class=3D"">SRS + WBRT vs. Resection + WBRT</P> <P class=3D"">SRS vs. Resection + WBRT</P> <P class=3D"">Other Comparisons</P> <P class=3D"">Multi-dose SRS vs. WBRT</P> <P class=3D"">Multi-dose SRS vs. Resection + WBRT or local = radiotherapy=20 (RT)</P> <P class=3D"">Resection + WBRT vs. = Resection + SRS</P> <P class=3D"">Single dose SRS =B1 WBRT vs. Multi-dose=20 SRS + WBRT</P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, Cochrane = Database of=20 Abstracts of Reviews of Effects. A broad search strategy using a = combination of=20 subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR30">30</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 (local=20 RT =3D fractionated radiotherapy localized to the = tumor):=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>WBRT vs. WBRT + SRS</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS vs. WBRT + SRS</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS vs. WBRT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS =B1 WBRT or local RT vs. = Resection =B1 WBRT=20 or local RT</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>SRS =B1 Resection vs. = WBRT =B1 Resection</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>Single dose SRS =B1 WBRT vs. Multi-dose=20 SRS =B1 WBRT</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with newly diagnosed brain = metastases ≥5=20 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=20 newly diagnosed brain metastases. 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 newly diagnosed brain metastases.=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 was used = to rate=20 the quality of randomized trials [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR31">31</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR32">32</A></CITE>].=20 The quality of comparative studies using non-randomized designs was = evaluated=20 using eight items selected 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 AANS/CNS criteria. These = criteria=20 are provided in the methodology paper to this guideline series. = </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV> <DIV class=3D""><A name=3DSec8></A> <DIV class=3DHeading3>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">Overall 16,966 publications were screened. Fifty-six = publications=20 passed through the title and abstract screening to the full text = screening=20 level. Ultimately, 32 publications (31 primary studies and one companion = paper)=20 met the eligibility criteria. Figure <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Fig1">1</A>=20 outlines the flow of the studies through the review process.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_73_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/7w84227x88442213/MediaObjects/= 11060_2009_73_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> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Whole brain radiotherapy alone versus whole brain=20 radiotherapy plus stereotactic radiosurgery</DIV> <DIV class=3DPara> <DIV class=3D"">Two prospective RCTs (class I evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>]=20 and one retrospective cohort study with historical controls (class III = evidence)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 evaluated WBRT alone vs. WBRT + SRS for the initial management = of=20 patients with solid metastatic brain tumors. One prospective cohort = study (class=20 II evidence) evaluated WBRT alone vs. WBRT + SRS for the = initial=20 management of patients with solid metastatic brain tumors in two arms of = a=20 three-arm study that also evaluated SRS alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>).=20 One retrospective cohort study (class II evidence) evaluated WBRT alone = vs.=20 WBRT + SRS as two of the arms in a four arm study that also = included=20 SRS alone and surgery alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 In all five of these unique studies, only single-dose SRS was evaluated, = and the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Evidence = table=97summary of primary studies </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author (year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design </P> <P class=3D"">Evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Interventions</P></TH> <TH align=3Dleft> <P class=3D"">Population</P></TH> <TH align=3Dleft> <P class=3D"">Median survival</P></TH> <TH align=3Dleft> <P class=3D""># Pts with recurrence/Progression<SUP>c</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=3D7> <P class=3D"">WBRT vs. WBRT + SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Andrews (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 167) </P> <P class=3D"">G2: WBRT + SRS = (<I>n</I> =3D 164) </P></TD> <TD align=3Dleft> <P class=3D"">1=963 BM</P></TD> <TD align=3Dleft> <P class=3D"">Median survival overall:</P> <P class=3D"">G1: 6.5 months</P> <P class=3D"">G2: 5.7 months (Survival curves: log-rank;=20 <I>p</I> =3D NS </P> <P class=3D"">Median survival for single BM pts:</P> <P class=3D"">G1: 4.9 months</P> <P class=3D"">G2: 6.5 months (Survival curves: log-rank;<I>=20 p</I> =3D 0.0393) </P></TD> <TD align=3Dleft> <P class=3D"">Central review assessed 1 yr local control:</P> <P class=3D"">G1: 71%</P> <P class=3D"">G2: 82% (<I>p</I> =3D 0.01) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank;<I> = p</I> =3D 0.0132)=20 </P> <P class=3D"">Overall in brain:Median: NR</P> <P class=3D"">(BR curves: log-rank;<I> p</I> =3D NS) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Kondziolka (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 14) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 13) = </P></TD> <TD align=3Dleft> <P class=3D"">2=964 BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7.5 months</P> <P class=3D"">G2: 11 months (Survival curves: log-rank;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 yr local failure rate:</P> <P class=3D"">G1: 100%</P> <P class=3D"">G2: 8%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 36 months (LR curves: log-rank;<I>=20 p</I> =3D 0.0016 </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 5 months</P> <P class=3D"">G2: 34 months (Test unclear; = <I>p</I> =3D 0.002)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Sanghavi (2001) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 1200 </P> <P class=3D"">G2: WBRT + SRS = (<I>n</I> =3D 502) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: RPA class I 7.1 months</P> <P class=3D"">G2: RPA class I 16.1 months</P> <P class=3D"">(Greenwood=92s estimates;<I> = p</I> < 0.05) </P> <P class=3D"">G1: RPA class II 4.2 months</P> <P class=3D"">G2: RPA class II 10.3 months</P> <P class=3D"">(Greenwood=92s estimates;<I> = p</I> < 0.05) </P> <P class=3D"">G1: RPA class III 2.3 months</P> <P class=3D"">G2: RPA class III 8.7 months</P> <P class=3D"">(Greenwood=92s estimates;<I> = p</I> < 0.05) </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 colSpan=3D7> <P class=3D"">WBRT vs. SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Datta (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 67) </P> <P class=3D"">G2: SRS =B1 WBRT = (<I>n</I> =3D 53) [12/53=20 (23%) had WBRT prior to SRS] </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 6 months (Survival curves: log-rank;<I>=20 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""> Kocher (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 117) </P> <P class=3D"">G2: WBRT (<I>n</I> =3D 138) </P></TD> <TD align=3Dleft> <P class=3D"">1=963BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: RPA class I 25.4 months</P> <P class=3D"">G2: RPA class I 4.7 months (Test not = reported;<I>=20 p</I> < 0.0001) </P> <P class=3D"">G1: RPA class II 5.9 months</P> <P class=3D"">G2: RPA class II 4.1 months</P> <P class=3D"">(Test not reported;<I> p</I> < 0.04) = </P> <P class=3D"">G1: RPA class III 4.2 months</P> <P class=3D"">G2: RPA class III 2.5 months (Test not = reported;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR by treatment groups</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Lee (2008) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 8) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 7) </P></TD> <TD align=3Dleft> <P class=3D"">BM from epithelial ovarian cancer</P></TD> <TD align=3Dleft> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 29 months (Survival curves; log-rank:<I>=20 p</I> =3D 0.0061) </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""> Rades (2007) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 91) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 95) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7 months</P> <P class=3D"">G2: 13 months (Survival curves: log-rank;<I>=20 p</I> =3D 0.045) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local brain control rate:</P> <P class=3D"">G1: 26%</P> <P class=3D"">G2: 64%</P> <P class=3D"">1 year distant brain control rate:</P> <P class=3D"">G1: 66%</P> <P class=3D"">G2: 61%</P> <P class=3D"">1 yr overall brain control rate:</P> <P class=3D"">G1: 23%</P> <P class=3D"">G2: 49%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: Not reported by treatment group</P> <P class=3D"">(LR curves: log-rank;<I> p</I> < 0.001) = </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">Median: Not reported by treatment group</P> <P class=3D"">(DR curves: log-rank;<I> p</I> =3D NS) = </P> <P class=3D"">Anywhere in brain:</P> <P class=3D"">Median: Not reported by treatment group</P> <P class=3D"">(BR curves: log-rank;<I> p</I> =3D 0.005) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">WBRT vs. SRS vs. WBRT + SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Li (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Prospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 19) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 23) </P> <P class=3D"">G3: SRS + WBRT (<I>n</I> =3D 18) = </P></TD> <TD align=3Dleft> <P class=3D"">Lung cancer BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 5.7 months</P> <P class=3D"">G2: 9.3 months</P> <P class=3D"">G3: 10.6 months</P> <P class=3D"">Survival curves 3 groups: log-rank;<I>=20 p</I> < 0.0001 </P> <P class=3D"">Survival curves G2 vs. G3: log-rank;<I> = p</I> =3D NS=20 </P></TD> <TD align=3Dleft> <P class=3D""># of pts with the following tumor response:</P> <P class=3D"">G1: CR or PR 14/29 (48%)</P> <P class=3D"">no change 11/29 (38%)</P> <P class=3D"">progression 4/29 (14%)</P> <P class=3D"">G2: CR or PR 20/23 (87%)</P> <P class=3D"">no change 3/23 (13%)</P> <P class=3D"">progression 0/23</P> <P class=3D"">G3: CR or PR 16/18 (89%)</P> <P class=3D"">no change 2/18 (11%)</P> <P class=3D"">progression 0/18 (3 groups:<I> = p</I> =3D 0.004) (G2=20 vs. G3:<I> p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 4.0 months</P> <P class=3D"">G2: 6.9 months</P> <P class=3D"">G3: 8.6 months (LR curves of 3 groups: = log-rank;<I>=20 p</I> =3D 0.0000) </P> <P class=3D"">(LR curves G2 vs. G3: log-rank;<I> = p</I> =3D NS) </P> <P class=3D"">At distant sites in brain:</P> <P class=3D"">G1: 4.1 months</P> <P class=3D"">G2: 6.7 months</P> <P class=3D"">G3: 8.6 months (DR curves of 3 groups: = log-rank;<I>=20 p</I> =3D 0.0000) (DR curves G2 vs. G3: log-rank;=20 p =3D 0.0392) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">SRS vs. WBRT + SRS</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Aoyama (2006, 2007) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 67) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 65) = </P></TD> <TD align=3Dleft> <P class=3D"">1=964BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.0 months</P> <P class=3D"">G2: 7.5 months (Survival curves: log-rank;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control rate (by lesion):</P> <P class=3D"">G1: 73%</P> <P class=3D"">G2: 89%</P> <P class=3D"">1 year DR rate:</P> <P class=3D"">G1: 64%</P> <P class=3D"">G2: 42%</P> <P class=3D"">1 yr BR rate:</P> <P class=3D"">G1: 76%</P> <P class=3D"">G2: 47%</P></TD> <TD align=3Dleft> <P class=3D"">At distant brain site:</P> <P class=3D"">Median: NR(DR curves: log-rank;<I> = p</I> =3D 0.003)=20 </P> <P class=3D"">Overall in brain:</P> <P class=3D"">Median: NR (BR curves: log-rank;<I>=20 p</I> < 0.001) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Chidel (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study </P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 78) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 57) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 10.5 months</P> <P class=3D"">G2: 6.4 months (Survival curves: log-rank;<I>=20 p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">2 year local control rate:</P> <P class=3D"">G1: 52%</P> <P class=3D"">G2: 80%</P> <P class=3D"">2 year freedom from DR rate: G1: 48%</P> <P class=3D"">G2: 74%</P> <P class=3D"">2 year freedom from BR rate:</P> <P class=3D"">G1: 34%</P> <P class=3D"">G2: 60%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank;<I> = p</I> =3D 0.034)=20 </P> <P class=3D"">At distant brain site:</P> <P class=3D"">Median: NR (DR curves: log-rank;<I> = p</I> =3D NS) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 9.2 months</P> <P class=3D"">G2: 35.1 months (BR curves: log-rank;<I>=20 p</I> =3D 0.027) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Combs (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 10) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 13) = </P> <P class=3D"">G3: SRS for recurrence (<I>n</I> =3D 39) = </P></TD> <TD align=3Dleft> <P class=3D"">Beast cancer BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9 months</P> <P class=3D"">G2: 6 months</P> <P class=3D"">G3:19 months (G1 vs. G2 survival curves = log-rank:<I>=20 p</I> =3D 0.036) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 6.5 months</P> <P class=3D"">G2: 4.0 months</P> <P class=3D"">G3: 9 months (G1 vs. G2 LR curves: log-rank;<I> = p</I> =3D NS) </P> <P class=3D"">At distant brain site:</P> <P class=3D"">G1: 6.5 months</P> <P class=3D"">G2: 4.0 months</P> <P class=3D"">G3: 7 months (G1 vs. G2 DR curves: log-rank;<I> = p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hoffman (2001) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 41) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 19) = </P> <P class=3D"">G3: SRS for recurrent BM (<I>n</I> =3D 53) = </P></TD> <TD align=3Dleft> <P class=3D"">Lung cancer BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 13.9 months</P> <P class=3D"">G2: 14.5 months</P> <P class=3D"">G3: 10.0 months (G1 vs. G2 cox univariate;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR:</P> <P class=3D"">G1: 62%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: 36%</P> <P class=3D"">1 year freedom from DR:</P> <P class=3D"">G1: 33%</P> <P class=3D"">G2: 78%</P> <P class=3D"">G3: 55%</P> <P class=3D"">1 year freedom from BR:</P> <P class=3D"">G1: 13%</P> <P class=3D"">G2: 67%</P> <P class=3D"">G3: 27%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 22.2 months</P> <P class=3D"">G2: Not reached</P> <P class=3D"">G3: 9.2 months (G1 vs. G2 LR curves: log-rank;=20 <I>p</I> =3D NS) </P> <P class=3D"">At distant brain site:</P> <P class=3D"">G1: 8.0 months</P> <P class=3D"">G2: Not reached</P> <P class=3D"">G3: 16.5 months (G1 vs. G2 DR curves: log-rank; = <I>p</I> =3D 0.015) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 6.9 months</P> <P class=3D"">G2: 15.0 months</P> <P class=3D"">G3: 5.8 months (G1 vs. G2 BR curves: log-rank;=20 0.002)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Jawahar (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR43">43</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 43) </P> <P class=3D"">G2: SRS + WBRT (<I>n</I> =3D 18) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR by treatment group (Survival curves: = log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Local tumor control:</P> <P class=3D"">Reported no significant difference between groups = [data:=20 NR]</P> <P class=3D"">Distant tumor recurrence:</P> <P class=3D"">Reported no significant difference between groups = [data:=20 NR]</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Noel (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 34) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 22) = </P> <P class=3D"">G3: SRS for recurrence BM = (<I>n</I> =3D 36) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7 months</P> <P class=3D"">G2: 14 months</P> <P class=3D"">G3: 8 months (G1 vs. G2 survival curves: = log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control rate:</P> <P class=3D"">G1: 78%</P> <P class=3D"">G2: 94%</P> <P class=3D"">G3: 86%</P></TD> <TD align=3Dleft> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 13 months</P> <P class=3D"">G2: 24 months (G1 vs. G2 BR curves: NR)</P> <P class=3D"">G3: Not reached</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Pirzkall (1998) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 158) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 78) = </P></TD> <TD align=3Dleft> <P class=3D"">1=963 BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR by treatment group</P> <P class=3D"">1 year survival rates:</P> <P class=3D"">G1: 19%</P> <P class=3D"">G2: 30% (Survival curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control rate:</P> <P class=3D"">G1: 89%</P> <P class=3D"">G2: 92%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median time: NR (LR curves: log-rank; = <I>p</I> =3D NS)=20 </P> <P class=3D"">At distant brain site:</P> <P class=3D"">G1: 4.3 months</P> <P class=3D"">G2: 5.4 months (<I>p</I> =3D NR) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Sneed (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR46">46</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 62) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 43) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 11.3 months</P> <P class=3D"">G2: 11.1 months (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 13/62 (21%)</P> <P class=3D"">G2: 7/43 (16%)</P> <P class=3D"">At distant brain sites</P> <P class=3D"">G1: 31/62 (50%)</P> <P class=3D"">G2: 12/43 (28%)</P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 36/62 (58%)</P> <P class=3D"">G2: 16/43 (37%)</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">G1: 21.0 months</P> <P class=3D"">G2: Not reached (LR curves: log-rank; = <I>p</I> =3D NS)=20 </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">G1: 8.5 months</P> <P class=3D"">G2: 16.8 months (DR curves: log-rank;=20 <I>p</I> =3D 0.03) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">G1: 8.3 months</P> <P class=3D"">G2: 15.9 months (BR curves: log-rank;=20 <I>p</I> =3D 0.008) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Sneed (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR47">47</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 268) </P> <P class=3D"">G2: WBRT + SRS = (<I>n</I> =3D 301) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.2 months</P> <P class=3D"">G2: 8.6 months (Univariate Cox; = <I>p</I> =3D NS)=20 </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""> Varlotto (2005) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 40) </P> <P class=3D"">G2: WBRT + SRS (<I>n</I> =3D 70) = </P></TD> <TD align=3Dleft> <P class=3D"">Pts surviving >1 year after SRS for = BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR by group (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year local control (by lesion):</P> <P class=3D"">G1: 84%</P> <P class=3D"">G2: 93%</P> <P class=3D"">1 year distant recurrence rates:</P> <P class=3D"">G1: 26%</P> <P class=3D"">G2: 21%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank; = <I>p</I> =3D 0.03)=20 </P> <P class=3D"">At distant brain sites:</P> <P class=3D"">Median: NR (DR curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">SRS vs. Surgery +WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic (2008) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery + WBRT = (<I>n</I> =3D 33) </P> <P class=3D"">G2: SRS (<I>n</I> =3D 31) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9.5 months</P> <P class=3D"">G2: 10.3 months (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from local = recurrence/progression=20 rates:</P> <P class=3D"">G1: 82%</P> <P class=3D"">G2: 97%</P> <P class=3D"">1 year distant recurrence/progression = rates:</P> <P class=3D"">G1: 3%</P> <P class=3D"">G2: 26%</P></TD> <TD align=3Dleft> <P class=3D"">Median time to local recurrence in brain: Not = reported (LR=20 curves: log-rank; <I>p</I> =3D NS) </P> <P class=3D"">Median time to distant recurrence in brain: Not = reported (DR=20 curves: log-rank; <I>p</I> < 0.05) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Muacevic (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR58">58</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 35 weeks</P> <P class=3D"">G2: 68 weeks (Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR rate:</P> <P class=3D"">G1: 83%</P> <P class=3D"">G2: 75%</P> <P class=3D"">1 year 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 (LR curves: log-rank;=20 <I>p</I> =3D NS) </P> <P class=3D"">At distant site: NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rades (2007) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS (<I>n</I> =3D 94) </P> <P class=3D"">G2: Surgery + WBRT = (<I>n</I> =3D 112)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P> <P class=3D"">1 year survival rate:</P> <P class=3D"">G1: 54%</P> <P class=3D"">G2: 38% (Survival curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR rate:</P> <P class=3D"">G1: 64%</P> <P class=3D"">G2: 56%</P> <P class=3D"">1 year freedom from BR rate:</P> <P class=3D"">G1: 49%</P> <P class=3D"">G2: 44%</P></TD> <TD align=3Dleft> <P class=3D"">At original site:</P> <P class=3D"">Median: NR (LR curves: log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">Overall in brain:</P> <P class=3D"">Median: NR (BR curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">SRS + WBRT vs. Surgery +WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bindal (1996) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1:=20 Surgery =B1 WBRT<SUP>a</SUP>(n =3D 62)[matched = to G2] </P> <P class=3D"">G2: SRS =B1 WBRT<SUP>a</SUP> = (<I>n</I> =3D 31)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 16.4 months</P> <P class=3D"">G2: 7.5 months (Survival curves:log-rank;=20 <I>p</I> =3D 0.0018) </P></TD> <TD align=3Dleft> <P class=3D"">1 year freedom from LR rate:</P> <P class=3D"">G2 poorer than G1 [Data: NR]</P> <P class=3D"">1 year 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 (LR curves: log-rank;=20 <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 (DR curves: log-rank;=20 <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Garell (1999) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8 months</P> <P class=3D"">G2: 12.5 months (Survival curves:log-rank;=20 <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""> O=92Neill (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: Surgery<SUP>a</SUP> =B1 WBRT=20 (<I>n</I> =3D 74) </P> <P class=3D"">G2: SRS<SUP>a</SUP> =B1 WBRT = (<I>n</I> =3D 23)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">Median survival: NR</P> <P class=3D"">1 year survival rate:</P> <P class=3D"">G1: 62%</P> <P class=3D"">G2: 56% (Survival curves: log-rank; = <I>p</I> =3D NS)=20 </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 (<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> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schoggl (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9 months</P> <P class=3D"">G2: 12 months (Survival curves: test = unclear<SUP>b</SUP>;=20 <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 (LR curves: test = unclear<SUP>b</SUP>=20 <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 (DR curves: test = unclear<SUP>b</SUP>=20 <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Other</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> De Salles (1993) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR62">62</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: SRS =B1 WBRT = (<I>n</I> =3D 19) </P> <P class=3D"">G2: SFR =B1 WBRT = (<I>n</I> =3D 7) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">Average survival:</P> <P class=3D"">G1: 8 months</P> <P class=3D"">G2: 7 months (<I>p</I>-value: NR) </P></TD> <TD align=3Dleft> <P class=3D"">At distant sites in brain:</P> <P class=3D"">G1: 4/19 (21%)</P> <P class=3D"">G2: NR</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ikushima (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR64">64</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1 : SFR (<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) = [RT =3D WBRT or=20 local] </P></TD> <TD align=3Dleft> <P class=3D"">RCC BM</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 (Univariate = analysis<SUP>d</SUP>:G1 vs.=20 G2 + G3: <I>p</I> =3D 0.05) </P></TD> <TD align=3Dleft> <P class=3D"">1 year 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 (LR curves: log-rank; = <I>p</I> =3D NS)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Lindvall (2005) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR63">63</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: SFR (<I>n</I> =3D 47) </P> <P class=3D"">G2: WBRT + SRS or SFR = (<I>n</I> =3D 14)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 5.0 months</P> <P class=3D"">G2: 5.0 months(Survival curves: log-rank;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Local response (by lesion) in the pts with available = data:</P> <P class=3D"">G1: stable 37/44 (84%) progression 7/44 (16%)</P> <P class=3D"">G2: stable 11/11 (100%) progression 0/11=20 (<I>p</I> =3D NS) </P> <P class=3D""># of pts with recurrence at distant sites:</P> <P class=3D"">G1: 8/32 (25%)</P> <P class=3D"">G2: 0/11 (<I>p</I> =3D 0.0005) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Serizawa (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR61">61</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT =B1 surgical resection=20 (<I>n</I> =3D 34) </P> <P class=3D"">G2: SRS =B1 surgical resection=20 (<I>n</I> =3D 62) </P></TD> <TD align=3Dleft> <P class=3D"">NSCLC BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 199 days</P> <P class=3D"">G2: 377 days (Survival curves: log-rank:=20 <I>p</I> =3D 0.0158) </P></TD> <TD align=3Dleft> <P class=3D"">1 year tumor control rates:</P> <P class=3D"">G1: NR</P> <P class=3D"">G2: 94.8%</P></TD> <TD align=3Dleft> <P class=3D"">At distant sites in brain:</P> <P class=3D"">G1: 539 days</P> <P class=3D"">G2: 422 days (DR curves: log-rank;=20 <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shinoura (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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)=20 [RT =3D WBRT or local] </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 8.2 months</P> <P class=3D"">G2: 34.4 months (Survival curves: log-rank;=20 <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%) (<I>p</I> =3D NR) </P></TD> <TD align=3Dleft> <P class=3D"">Mean time to recurrence at original site:</P> <P class=3D"">G1: 7.2 months</P> <P class=3D"">G2: 25 months (LR curves: log-rank;=20 <I>p</I> =3D 0.0199) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Wang (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</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"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 43.0 weeks</P> <P class=3D"">G2: 37.0 weeks</P> <P class=3D"">G3: 67.0 weeks</P> <P class=3D"">G4: 91.0 weeks (Survival curves: log-rank;=20 <I>p</I> < 0.00001) </P></TD> <TD align=3Dleft> <P class=3D"">Local tumor control at 1 month:</P> <P class=3D"">G1: 89%</P> <P class=3D"">G2: 88%</P> <P class=3D"">G3: 93%</P> <P class=3D"">G4: 96% (<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>BM</I> Brain metastases, <I>BR</I> Brain = recurrence=20 (local + distant), <I>CR</I> Complete response,=20 <I>DR</I> Distant recurrence in brain,<I> G1</I> Group 1,=20 <I>G2</I> Group 2, <I>G3</I> Group 3, <I>G4</I> Group 4,=20 <I>LR</I> Local recurrence at original site in brain,=20 <I>NSCLC</I> Non-small cell lung cancer, <I>NR</I> Not = reported,=20 <I>NS</I> Not significant, <I>PR</I> Partial response,=20 <I>Pts</I> Patients, <I>RCC</I> Renal cell carcinoma,=20 <I>RCT</I> Randomized control trial, <I>RPA</I> Recursive = partitioning=20 analysis, <I>RT</I> Radiotherapy, <I>SFR</I> Stereotactic = fractionated=20 radiotherapy, <I>SRS</I> Stereotactic radiosurgery,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>WBRT use similar at baseline in both groups=20 </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>b</SUP> Either log-rank or Wilcoxon test = </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>c</SUP> Number of pts with recurrence/progression = of brain=20 metastases, unless otherwise specified </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>d</SUP> Univariate analysis using Cox proportional = hazard=20 model </DIV></DIV></DIV></DIV></DIV> <P class=3D"">The first RCT is a Radiation Therapy Oncology Group (RTOG) = multi-center trial led by Andrews et al., published in 2004 = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 The trial randomized adults with a Karnofsky performance status=20 (KPS) ≥ 70 with 1=963 solid brain metastases with a = maximum diameter of=20 4 cm for the largest and ≤3 cm for the remainder. = Patients were=20 stratified by number of metastases and extent of extra-cranial disease. = WBRT and=20 SRS doses were standard. Overall follow-up was a median of = 12 months.=20 Patient groups were well matched for sex, age (19=9690 years), = histology,=20 KPS, and mini-mental status exam (MMSE) score. There were 164 patients = in the=20 WBRT + SRS arm (of which 31/164 (19%) did not receive their = planned=20 SRS) and 167 patients in the WBRT alone arm (of which 28/167 (17%) = received=20 salvage SRS). The primary endpoint was median survival. Secondary = endpoints=20 included tumor control at 1 year, KPS and MMSE at 6 months and = cause=20 of death (neurologic vs. non-neurologic). This trial can be criticized = for a=20 large bilateral crossover rate in an intent-to-treat model, no follow-up = neuroimaging review on 43% of patients, and inclusion of tumors = >3 cm=20 diameter which are known to be less favorable for SRS but were included = in the=20 original RTOG 90-05 trial and were included for that reason (refer to = the=20 surgical resection guideline paper by Kalkanis et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR27">27</A></CITE>].=20 Nevertheless, this trial demonstrated significantly better survival for = patients=20 with single metastatic tumors (<I>p</I> =3D 0.01), superior = local=20 control for patients with 1=963 metastatic brain tumors=20 (<I>p</I> =3D 0.01), and improved KPS for patients with 1=963 = metastatic=20 brain tumors in the WBRT + SRS arm. The last two conclusions = were=20 secondary endpoints assessed with post hoc analysis and thus, are not as = strong=20 as the single tumor survival conclusion. There was no significant = difference=20 between groups in median survival for patients with 2=963 brain tumors, = MMSE at=20 6 months, incidence of neurologic cause of death, or adverse = therapeutic=20 events [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 However, because of the large follow-up loss in this study, no = conclusion can be=20 assured. </P> <P class=3D"">The second RCT is a single institution study from the = University of=20 Pittsburgh led by Kondziolka et al., published in 1999 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>].=20 The trial randomized adults with a KPS ≥ 70 with 2=964 = solid metastatic=20 brain tumors, each ≤2.5 cm in mean diameter. WBRT and SRS = doses were=20 standard. Overall follow-up was not reported. Patient groups were well = matched=20 for sex, age (33=9677 years), histology, number of brain tumors, = KPS score,=20 and extent of systemic disease. There were 14 patients in the WBRT arm = and 13 in=20 the WBRT + SRS arm. All patients completed the treatment in = their=20 intent-to-treat arm. Since the primary endpoint was imaging-defined = local=20 control, no patient received salvage SRS until they were censored for = analysis.=20 Secondary endpoints included median survival, and time to = recurrence/progression=20 at the original tumor sites. The study was stopped at the 60% accrual = point due=20 to an overwhelmingly positive tumor control difference at interim = analysis. This=20 trial demonstrated significantly better local control rates measured in = terms of=20 local failure at 1 year (8 vs. 100%) and median time to=20 recurrence/progression at original site (36 vs. 6 months) for = patients in=20 the WBRT + SRS arm. Since the study was stopped at 60% = accrual, its=20 statistical power to assess differences in median survival was limited. = Despite=20 a large trend of 11 vs. 7.5 months favoring WBRT + SRS, = this=20 result did not achieve statistical significance due to the relatively = low number=20 of patients. Functional performance outcome, cause of death, and = incidence of=20 adverse events were not reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>].=20 </P> <P class=3D"">In the three arm prospective cohort study by Li = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 recruitment was restricted to patients with both small cell- and = non-small-cell=20 lung cancer (NSCLC) and single brain metastases ≤4.5 cm = diameter in adults=20 with a KPS ≥ 60, two of the three arms were WBRT=20 (<I>n</I> =3D 19) vs. WBRT + SRS = (<I>n</I> =3D 18).=20 Groups were similar in terms of sex, age, histology, extent of = extracranial=20 disease, and KPS score. WBRT doses and SRS doses were standard. The = median=20 survival advantage for WBRT + SRS was highly significant=20 (<I>p</I> < 0.0001) as was the advantage for local tumor = control=20 (<I>p</I> =3D 0.004) and median time to progression for the = treated=20 tumor (<I>p</I> < 0.00001). </P> <P class=3D"">The four arm retrospective cohort study by Wang = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 evaluated adult patients with 1=966 metastases of varying histologies, = each=20 <4 cm in diameter, and a KPS of 40=9690; two of the four arms = were WBRT=20 alone (<I>n</I> =3D 120) vs. WBRT + SRS=20 (<I>n</I> =3D 83). Groups were similar in terms of sex and = age. Primary=20 histology, KPS score, and extent of systemic disease were not reported = by=20 treatment group. The WBRT + SRS had significantly more = patients with=20 multiple brain tumors (50/83) than the WBRT alone arm (34/120). WBRT = doses and=20 SRS doses were standard. While 1 month local tumor control rates = were=20 similar between groups (95.6 vs. 88.3%), median survival significantly = favored=20 the WBRT + SRS group (91 vs. 37 weeks). </P> <P class=3D"">Sanghavi et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 performed a large retrospective cohort trial = (<I>n</I> =3D 502) of=20 patients with varying histologies with historical controls based on = recursive=20 partitioning analysis (RPA) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR37">37</A></CITE>]=20 of a database of patients from RTOG trials = (<I>n</I> =3D 1,200) where=20 patients received WBRT alone. Groups were stratified by RPA class. = Groups were=20 similar in age, and extent of extracranial disease. The WBRT group had = slightly=20 lower KPS scores, while the WBRT + SRS group had a greater = percentage=20 of radioresistant histologies (e.g., melanoma). They found statistically = significant improvements in survival for patients in all three RPA = classes,=20 suggesting a survival benefit for SRS + WBRT even in patients = with=20 >1 metastatic brain tumor, the presence of systemic disease, and low = KPS=20 score. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy plus stereotactic radiosurgery</DIV> <P class=3D"">One prospective RCT (class I evidence) with a companion = paper=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>],=20 and nine retrospective cohort studies (class II evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 evaluated SRS alone vs. WBRT + SRS for the initial management = of=20 patients with solid metastatic brain tumors. One prospective cohort = study (class=20 II evidence) evaluated SRS alone vs. WBRT + SRS for the = initial=20 management of patients with solid metastatic brain tumors in two arms of = a=20 three-arm study that also evaluated WBRT alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>).=20 One retrospective cohort study (class II evidence) evaluated SRS alone = vs.=20 WBRT + SRS as two of the arms in a four arm study that also = included=20 WBRT alone and surgery alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 In all 12 of these unique studies, only single-dose SRS was evaluated, = and the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">The RCT is a multi-institutional study from Japan led by = Aoyama=20 et al., published in 2006 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>].=20 The trial randomized adults with a KPS ≥ 70 with 1=964 = solid brain=20 metastases with a maximum diameter of ≤3 cm. Follow-up was = 20.7 months=20 for the SRS arm and 30.5 months for the WBRT + SRS arm. = Isolated=20 WBRT and SRS alone doses were standard, however, the SRS dose was = reduced by 30%=20 in the WBRT + SRS arm relative to the SRS alone arm. Patient = groups=20 were similar in terms of sex, age, histology, number of tumors, extent, = and=20 stability of extracranial disease, primary tumor status, KPS score, and = MMSE=20 score. There were 67 patients in the SRS alone arm (of which 2/67 (3%) = did not=20 receive SRS, and 11/67 (16%) received WBRT as a salvage therapy) and 65 = in the=20 WBRT + SRS arm (of which 6/65 (9%) did not receive SRS, 2/65 = (3%) did=20 not receive WBRT, and 10/65 (15%) received additional salvage SRS). The = primary=20 endpoint was median survival. Secondary endpoints included 1 year = tumor=20 control rate, 1 year recurrence rate at untreated sites, neurologic = cause=20 of death, 1 year KPS score, 1 year MMSE score, and adverse = event rate.=20 This trial can be criticized for a large bilateral crossover rate in an=20 intent-to-treat model. Results revealed no significant difference = between study=20 groups for median survival (8.0 vs. 7.5 months), 1 year local = control=20 rate (72.5 vs. 88.7%), neurologic cause of death, 1 year KPS score, = MMSE=20 score, or acute or late neurotoxicity. However, the 1 year chance = of=20 recurrence locally (27.5 vs. 11.3%), at a distant site (63.7 vs. 41.5%), = or=20 anywhere in the brain (76.4 vs. 46.8%) was significantly greater for the = SRS=20 alone arm than the WBRT + SRS arm, as was the chance of = requiring=20 additional salvage therapy in the form of either SRS or WBRT (43.3 vs. = 15.4%).=20 In a second, secondary endpoint analysis publication from the same study = looking=20 at the 70% subset of patients with initial and follow-up MMSE = examinations, and=20 then restricting analysis still further to the 62% of patients with=20 pre-treatment MMSE scores of ≥27 or who improved on follow-up to = MMSE scores=20 ≥27, the addition of up-front WBRT significantly increased the = time to MMSE=20 deterioration, which was often due to distant tumor recurrence [<CITE><A = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR39">39</A></CITE>].=20 </P> <P class=3D"">In the three arm prospective cohort study by Li = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 recruitment was restricted to patients with both SCLC and NSCLC, and = single=20 brain metastases ≤4.5 cm diameter in adults with a = KPS ≥ 60; two=20 of the three arms were SRS (<I>n</I> =3D 23) vs. = WBRT + SRS=20 (<I>n</I> =3D 18). Groups were similar in terms of sex, age, = histology,=20 extent of extracranial disease, and KPS score. WBRT doses and SRS doses = were=20 standard. There was no significant difference between the two groups in = terms of=20 median survival (9.3 vs. 10.6 months) or in terms of = recurrence/progression=20 at the treated site. Distant brain recurrence was not assessed. </P> <P class=3D"">Of the 10 retrospective cohort studies addressing this = comparison in=20 patients with both single and multiple brain metastases of varying = histologies,=20 nine are direct comparisons of SRS alone vs. WBRT + SRS = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 and one is a four arm retrospective cohort study with SRS and=20 WBRT + SRS as two of the four comparison arms [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 Of these 10 studies, eight show no significant difference in median = survival=20 between both treatment options with ranges for median survival of=20 7=9613.9 months and 6.4=9614.9 months, respectively [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 One study of patients with breast cancer brain metastases showed = improved median=20 survival of 9 vs. 6 months favoring SRS alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>],=20 and another studying tumors of varying histology showed improved median = survival=20 of 91 vs. 67 weeks favoring WBRT + SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 Of the 10 studies, only one (which studied only patients who had = survived=20 >1 year since treatment) revealed a statistically significant = increase=20 in local recurrence rate or reduced time to local recurrence [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 However, four revealed either increased distant brain or overall brain=20 recurrence rates and/or reduced time to distant brain or overall brain=20 recurrence [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>].=20 On the other hand, the study of patients who had survived = >1 year since=20 treatment suggested that while the median time to local = recurrence/progression=20 was significantly increased with SRS alone, the median time to distant=20 recurrence was not significantly different between the two arms = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy alone</DIV> <P class=3D"">No RCTs were identified that met the eligibility criteria = for this=20 treatment comparison. One prospective cohort study (class II evidence) = evaluated=20 SRS alone vs. WBRT alone for the initial management of patients with = solid=20 metastatic brain tumors in two arms of a three-arm study that also = evaluated=20 WBRT + SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>].=20 There were two retrospective cohort studies with concomitant control = groups=20 (class II evidence) that compared SRS alone vs. WBRT alone = (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>].=20 There were two retrospective cohort studies with historical controls = (class III=20 evidence) that compared SRS alone vs. WBRT alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>].=20 One retrospective cohort study (class II evidence) evaluated SRS alone = vs. WBRT=20 alone as two of the arms in a four arm study that also included=20 WBRT + SRS and surgery alone (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>].=20 In all of these unique studies, only single-dose SRS was evaluated, and = the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">The three arm prospective cohort study by Li et al. = (2000)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 evaluated adult patients with both SCLC and NSCLC, and single brain = metastases=20 ≤4.5 cm diameter in adults with a KPS ≥ 60, = two of the three arms=20 were SRS alone (<I>n</I> =3D 23) vs. WBRT alone=20 (<I>n</I> =3D 19). Groups were similar in terms of sex, age, = histology,=20 extent of extracranial disease, and KPS score. WBRT doses and SRS doses = were=20 standard. The SRS alone arm had significantly longer median survival = (9.3 vs.=20 5.7 months), neuroimaging tumor response (complete or partial = response 87=20 vs. 38%, and progression 0 vs. 14%), and median time to progression (6.9 = vs.=20 4.0 months). Distant brain recurrence was not assessed. </P> <P class=3D"">In the small retrospective cohort study by Lee et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>]=20 recruitment was restricted to patients with 1=9612 non-germ cell = epithelial=20 ovarian cancer brain metastases; 15 patients were treated with either = SRS alone=20 (<I>n</I> =3D 7) or WBRT alone (<I>n</I> =3D 8). = Groups were=20 poorly analyzed in terms of potentially relevant intergroup differences = and SRS=20 and WBRT dosing parameter was not provided. Despite these issues, the = authors=20 reported a significantly improved median survival outcome for the SRS = arm (29=20 vs. 6 months for WBRT alone). </P> <P class=3D"">In the large retrospective cohort study by Rades = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>]=20 186 patients with 1=963 brain metastases of varying histologies = ≤4 cm=20 diameter received either WBRT alone (<I>n</I> =3D 91) or SRS = alone=20 (<I>n</I> =3D 95). Groups were well matched for sex, age, RPA = class,=20 number of metastases, extent of extracranial disease, baseline = functional=20 performance, and histology. Median survival was significantly longer for = the SRS=20 alone group (13 vs. 7 months for WBRT alone). One-year local and = overall=20 brain control rates were likewise significantly better for the SRS alone = arm (64=20 vs. 26% and 49 vs. 23%, respectively). Distant brain control rates were = similar=20 for both groups (66% WBRT alone vs. 61% SRS alone). Toxicity rates were = similar=20 for both groups. </P> <P class=3D"">The four arm retrospective cohort study by Wang = et al.=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 evaluated adult patients with one or more brain metastases of varying=20 histologies, each <4 cm in diameter and a KPS > 50. = Two of=20 the four arms were SRS alone (<I>n</I> =3D 130) vs. WBRT alone = (<I>n</I> =3D 120). Groups were similar in terms of sex and = age. Primary=20 histology, KPS score, and extent of systemic disease were not reported = by=20 treatment group. The SRS treatment group had more patients with multiple = brain=20 tumors (50/83) than the WBRT alone arm (34/120). WBRT doses and SRS = doses were=20 standard. While 1 month local tumor control rates were similar = between=20 groups (93.3 vs. 88.3%), median survival significantly favored the SRS = group (67=20 vs. 37 weeks). </P> <P class=3D"">Kocher et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>]=20 performed a retrospective cohort trial of SRS = (<I>n</I> =3D 117)=20 compared against 138 WBRT historic control patients treated = 1=9620 years=20 previously at the same institution for brain metastases patients with = multiple=20 histologies and ≤3 tumors. Groups were similar in terms of sex and = age and were=20 stratified according to RPA classification which accounted for extent of = extra-cranial disease, number of tumors, and functional status [<CITE><A = href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR37">37</A></CITE>].=20 The SRS alone arm had more melanoma patients (27 vs. 6%). WBRT and SRS = doses=20 were standard. They reported significantly better results with SRS alone = for RPA=20 class I (25.4 vs. 4.7 months) and RPA class II (5.9 vs. = 4.1 months).=20 Difference in results for RPA class III (4.2 vs. 2.5 months) did = not reach=20 statistical significance. </P> <P class=3D"">Datta et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>]=20 performed a retrospective cohort trial of SRS =B1 WBRT (12/53 = (22.6%)=20 received WBRT) compared against 67 WBRT historic control patients = treated=20 1=963 years previously at the same institution for brain metastases = patients=20 with multiple histologies and <4 tumors each <30 cc in = volume. Groups=20 were similar in terms of sex and age, but differed in terms of lung and = breast=20 cancer histology (67.9 vs. 83.6%). Number of brain tumors, extent of=20 extracranial disease, and baseline performance status were not reported. = WBRT=20 and SRS doses were standard. They reported similar median survival of = only=20 6 months for both groups. </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Stereotactic radiosurgery plus WBRT versus = resection plus=20 WBRT</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There were four retrospective = cohort=20 studies (class II evidence) that evaluated SRS + WBRT vs.=20 resection + WBRT for the initial management of patients with = solid=20 metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 In all four of these unique studies, only single-dose SRS was evaluated, = and the=20 results cannot be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">Bindal et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>]=20 performed a retrospective cohort trial of 62 patients with single brain=20 metastases <3 cm in diameter treated with = resection =B1 WBRT=20 matched for sex, age, histology, KPS, and extent of disease to 31 = patients=20 undergoing SRS =B1 WBRT. WBRT was used in 66% of patients in = the first=20 arm and 71% of patients in the second. WBRT and SRS doses were standard. = In this=20 study, resection + WBRT achieved significantly longer median = survival=20 (16.4 vs. 7.5 months) and median time to recurrence, as well as=20 significantly lower rates of neurologic death (19 vs. 50%) and adverse = event=20 rates than SRS + WBRT. This study reported significantly lower = median=20 survival rates (only 7.5 months), as well as higher radiation = necrosis=20 rates (12.9%), than have ever been reported by other studies evaluating = single=20 brain metastases treated with SRS + WBRT. Given the poor = compliance=20 with completion of WBRT in both arms, this study warrants retrospective=20 down-grading to a class III evidence level, a study with flawed internal = validity. </P> <P class=3D"">In contrast, Garell et al., (1999) (1=962 tumors each = <3 cm diameter, <I>n</I> =3D 45), O=92Neill = et al., (2003)=20 (single tumors <3.5 cm, <I>n</I> =3D 97), and Schoggl=20 et al., (2000) (single tumors <3 cm diameter,=20 <I>n</I> =3D 133) each reported retrospective cohort studies = of patients=20 with brain metastases with very different results [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 Median survival was not significantly different but favored = SRS + WBRT=20 in two (12.5 vs. 8 months and 12 vs. 9 months, respectively) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>],=20 while 1 year survival was not significantly different but slightly = favored=20 resection + WBRT (62 vs. 56%) in the third [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>].=20 Median time to recurrence, incidence of neurologic death, and incidence = of acute=20 and long term adverse events were similar in both arms for the Mayo = Clinic study=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>].=20 Median time to local recurrence was significantly shorter (3.9 vs.=20 4.9 months) and the incidence of neurologic death was greater (21.8 = vs.=20 12.5%) in the resection + WBRT arm in the University of Vienna = study,=20 while adverse event rates were similar [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 Cause of death and adverse event rates were not reported for the = University of=20 Iowa study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>],=20 median time to recurrence was not reported in either the University of = Iowa or=20 the Mayo Clinic Studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>],=20 and functional performance results were not reported in any of the three = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus resection = plus=20 WBRT</DIV> <P class=3D"">One prospective RCT (class I evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>],=20 and two retrospective cohort studies (class II evidence) evaluated SRS = alone vs.=20 resection + WBRT for the initial management of patients with = solid=20 metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR58">58</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>].=20 One retrospective cohort study (class II evidence) evaluated SRS alone = vs.=20 resection + WBRT or local RT for the initial management of = patients=20 with solid metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 These four unique studies only evaluated single-dose SRS, and the = results cannot=20 be assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">Muacevic et al., (2008) performed a multicenter = prospective RCT=20 evaluating patients with single metastatic brain tumors, = ≤3 cm diameter=20 located in an operable site, treated with either SRS alone=20 (<I>n</I> =3D 31) or resection + WBRT=20 (<I>n</I> =3D 33) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>].=20 Groups were similar in terms of sex, age, histology, extent of systemic = disease,=20 and KPS score. WBRT and SRS doses were standard. There was no = significant=20 difference in outcome between the two groups in terms of functional = performance=20 outcome, rate of neurological death, or median survival (9.5 months = surgery + WBRT vs. 10.3 months SRS). However, the study = was=20 stopped early at only 25% accrual and was therefore underpowered to = detect=20 <15% differences in outcome between groups. The SRS patients did = experience=20 an increased number of distant tumor recurrences (25.8 vs. 3%), but = these=20 occurrences did not impact overall outcome when subsequent salvage SRS = was taken=20 into account. The resection + WBRT group did experience a=20 significantly larger number of grade 1 or 2 early and late complications = compared with the SRS group. </P> <P class=3D"">Rades et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>]=20 performed a retrospective cohort study of SRS alone = (<I>n</I> =3D 94)=20 vs. resection + WBRT (<I>n</I> =3D 112), for RPA = class I or II=20 patients with metastatic brain tumors ≤4 cm in diameter. = Groups were=20 similar in terms of sex, age, histology, number of brain tumors, extent = of=20 systemic disease, and KPS score. WBRT and SRS doses were standard. = Despite a=20 trend favoring SRS alone, there was no significant difference in outcome = between=20 groups for 1 year survival (54 vs. 38%). There was no significant=20 difference in outcomes for 1 year local recurrence rate (36 vs. = 44%) or=20 incidence of adverse events. Functional performance and neurologic cause = of=20 death outcomes were not reported. </P> <P class=3D"">Muacevic et al., (1999) performed a retrospective = cohort study=20 of SRS alone (<I>n</I> =3D 56) vs. resection + WBRT=20 (<I>n</I> =3D 52), for patients with single metastatic brain = tumors=20 ≤3.5 cm in diameter and with stable systemic disease = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR58">58</A></CITE>].Groups=20 were similar in terms of sex, age, extent of systemic disease, and KPS = score.=20 The SRS alone group had a slightly higher proportion of patients with = melanoma=20 (28.6 vs. 13.5%). WBRT and SRS doses were standard. Despite a trend = favoring=20 resection + WBRT, there was no significant difference in = outcome=20 between groups for median survival (35 vs. 68 weeks). There was no=20 significant difference in outcomes for 1 year local recurrence rate = (17 vs.=20 25%), median time to recurrence, functional performance score, or = incidence of=20 adverse events. </P> <P class=3D"">Shinoura et al., (2002) performed a retrospective = cohort study=20 of SRS alone (<I>n</I> =3D 52) vs. = resection + either WBRT or=20 local RT (<I>n</I> =3D 46, WBRT vs. local RT ratios not = reported) for=20 patients with one or more metastatic brain tumors <3 cm in = diameter=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 Groups were similar in terms of sex, age and histology, but the SRS = alone group=20 had more patients with multiple tumors (77 vs. 37%). Extent of = extracranial=20 disease and functional status were not reported. WBRT, local RT, and SRS = doses=20 were standard. They reported significantly longer median survival rates = (34.4=20 vs. 8.2 months) as well as longer mean time to recurrence rates (25 = vs.=20 7.2 months) for the resection + RT arm. Cause of death = and=20 incidence of adverse events were not reported. </P></DIV> <DIV class=3D""><A name=3DSec14></A> <DIV class=3DHeading3>Other comparisons</DIV> <P class=3D"">While our study group was interested in evaluating many = more=20 treatment comparisons (including the effectiveness of surgery plus SRS = vs.=20 resection plus WBRT, the effectiveness of substituting 2=965 dose SRS or = fractionated stereotactic radiotherapy (6=969 dose) for single dose SRS, = and the=20 effectiveness of substituting local fractionated radiotherapy for WBRT) = in=20 various paradigm combinations, none of these comparisons yielded more = than one=20 clinical study for analysis, and some none at all. As a result, few = conclusions=20 can be drawn at an evidence-based medicine clinical practice parameter = guideline=20 level. Those few studies where evidence exists are presented here for=20 completeness and interest sake and will be discussed further below in = the=20 section on =93<A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Sec26">Key=20 Issues for Further Investigation</A>=94. </P></DIV> <DIV class=3D""><A name=3DSec15></A> <DIV class=3DHeading3>Resection plus whole brain radiotherapy versus = resection=20 plus stereotactic radiosurgery</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 (class II evidence) that evaluated resection + WBRT or local = RT vs.=20 SRS alone for the initial management of patients with solid metastatic = brain=20 tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR61">61</A></CITE>].=20 In this study, only single-dose SRS was evaluated, and the results = cannot be=20 assumed to apply to 2=965 dose SRS [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR28">28</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR29">29</A></CITE>].=20 </P> <P class=3D"">Serizawa et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR61">61</A></CITE>]=20 performed a retrospective cohort study of resection + WBRT=20 (<I>n</I> =3D 34) vs. resection + SRS=20 (<I>n</I> =3D 62) for NSCLC patients with multiple brain = metastases=20 ≤3 cm in diameter in patients estimated to have at least = 2 months to=20 live. Groups were similar in terms of sex, age, number of brain tumors, = extent=20 of systemic disease, and KPS score. WBRT and SRS doses were standard. = The=20 resection + SRS alone group had significantly longer median = survival=20 (377 vs. 199 days). Unfortunately this result is difficult to = evaluate=20 given that the number of patients in the resection + WBRT arm = that had=20 resection of all tumors vs. resection of only some of the 1=9610 tumors = per=20 patient were not defined. The resection + SRS arm also showed=20 significantly longer neurological survival rates. Local tumor control = rates were=20 not reported. </P></DIV> <DIV class=3D""><A name=3DSec16></A> <DIV class=3DHeading3>Single-dose stereotactic radiosurgery versus = multi-dose=20 stereotactic radiosurgery plus whole brain radiotherapy</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 (class II evidence) that evaluated single-dose SRS alone vs. multi-dose=20 SRS + WBRT for the initial management of patients with solid=20 metastatic brain tumors (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR62">62</A></CITE>].=20 </P> <P class=3D"">De Salles et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR62">62</A></CITE>]=20 performed a retrospective cohort study of SRS alone = (<I>n</I> =3D 19)=20 vs. WBRT + multi-dose SRS (<I>n</I> =3D 7) in = patients with=20 multiple histologies with one or more metastatic brain tumors with = volumes=20 ranging from 0.09 to 51.84 cc (average volume 21.2 cc). Groups = were=20 similar in terms of sex and age, but the SRS alone arm had more melanoma = patients (16 vs. 0%) and had significantly more multiple brain tumor = patients=20 (34 tumors in 19 patients vs. seven tumors in seven patients). WBRT and=20 single-dose SRS doses were standard. The multi-dose SRS regimen was = 6 Gy=20 per dose given in 2=963 doses over 2=963 days. There was no = significant=20 difference in average survival between both arms (8 vs. 7 months); = however,=20 this study was underpowered to detect all but a very large difference.=20 </P></DIV> <DIV class=3D""><A name=3DSec17></A> <DIV class=3DHeading3>Multi-dose stereotactic radiosurgery versus whole = brain=20 radiotherapy plus either single- or multi-dose SRS</DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 with historical controls (class III evidence) that evaluated multi-dose = SRS vs.=20 WBRT for the initial management of patients with solid metastatic brain = tumors=20 (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR63">63</A></CITE>].=20 </P> <P class=3D"">Lindvall et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR63">63</A></CITE>]=20 performed a retrospective cohort study of multi-dose SRS alone vs.=20 WBRT + either single- or multi-dose SRS in patients with 1=963 = brain=20 metastases of varying histologies ranging in volume from 0.9 to = 41 cc=20 (median volume 5 cc). Groups were similar in terms of sex, extent = of=20 systemic disease, and KPS score. The multi-dose SRS arm had younger = patients=20 (61.7% ≥ 60 vs. 85.7% ≥ 60), fewer = melanoma patients (4.3=20 vs. 21.4%), fewer RPA class I patients (4.3 vs. 21.4%) and more patients = with=20 multiple brain tumors (23.4 vs. 14.2%). The WBRT dose was standard. The=20 multi-dose SRS regimen was 40 Gy in five 8 Gy doses. The = single- or=20 multi-dose boost regimen after WBRT was given in 1=963 doses of = 6=9612 Gy (mean=20 total dose 17 Gy). There was no significant difference in outcomes = between=20 groups for median survival (5 vs. 5 months) or local progression = (16 vs.=20 0%). There was a significantly larger distant recurrence rate for the = multi-dose=20 SRS alone arm (25 vs. 0%). </P></DIV> <DIV class=3D""><A name=3DSec18></A> <DIV class=3DHeading3>Fractionated stereotactic radiotherapy alone = versus=20 resection with either whole brain radiotherapy or local radiotherapy = versus=20 whole brain radiotherapy or local radiotherapy alone </DIV> <P class=3D"">No prospective studies were identified that met the = eligibility=20 criteria for this treatment comparison. There was one retrospective = cohort study=20 (class II evidence) that evaluated fractionated stereotactic = radiotherapy (FSR)=20 alone vs. resection plus WBRT or local RT vs. WBRT or local RT alone, = for the=20 initial management of patients with solid metastatic brain tumors = (Table <A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#Tab1">1</A>)=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR64">64</A></CITE>].=20 </P> <P class=3D"">Ikushima et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR64">64</A></CITE>]=20 performed a three arm retrospective cohort study in patients with 1=963 = renal cell=20 carcinoma brain metastases each ≤3 cm in diameter in adult = patients with an=20 Eastern Cooperative Oncology Group (ECOG) performance status of = ≤2, comparing=20 FSR (<I>n</I> =3D 10) vs. resection + either WBRT or = local RT=20 vs. WBRT or local RT alone. Patients were similar in terms of sex, age, = and=20 extent of extracranial disease. The FSR alone arm had more patients with = single=20 brain tumors, and the WBRT or local RT alone arm had less patients with = multiple=20 brain tumors than the resection + either WBRT or local RT arm = (90 vs.=20 70% and 50 vs. 36%, respectively). The WBRT or local RT alone arm had = more ECOG=20 performance status two patients than either the = resection + either=20 WBRT or local RT, or the FSR alone arm (50 vs. 18 vs. 0%). The WBRT and = local RT=20 doses were standard. The FSR regimen was 42 Gy in seven fractions=20 (6 Gy per fraction) over 2.3 weeks. While 1 year tumor = control=20 rates where similar for the FSR alone and the = resection + either WBRT=20 or local RT arms (89.6 vs. 87.5%), the FSR group had a significantly = longer=20 median survival (25.6 months) than either the = surgery + either=20 WBRT or local RT (18.7 months), or the WBRT or local RT alone arms=20 (4.3 months). </P></DIV></DIV> <DIV class=3D""><A name=3DSec19></A> <HR> <DIV class=3Dheading2>Summary and discussion</DIV> <DIV class=3D""><A name=3DSec20></A> <DIV class=3DHeading3>Whole brain radiotherapy alone versus whole brain=20 radiotherapy plus stereotactic radiosurgery</DIV> <P class=3D"">There is class I evidence from two RCTs with similar = inclusion=20 criteria that single-dose SRS + WBRT provides significantly = superior=20 local tumor control compared with WBRT alone for patients with 1=963 = brain=20 metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>]=20 and evidence from one of the RCTs that this applies in patients with up = to four=20 brain tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>].=20 One of the RCTs also showed improved KPS score results for the = single-dose=20 SRS + WBRT regimen [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 These results were achieved without an increased incidence of adverse=20 therapeutic events [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 While local control was a secondary endpoint, assessed post hoc in one = of the=20 RCTs [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>],=20 it was the primary endpoint in the second [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR25">25</A></CITE>],=20 which confirmed the conclusion. Based on the inclusion criteria for both = RCTs, a=20 level 1 recommendation for single-dose SRS + WBRT would only = have=20 external validity for patients with a KPS ≥ 70. </P> <P class=3D"">There is class I evidence from one RCT that single-dose=20 SRS + WBRT provides a significantly superior survival benefit = compared=20 with WBRT alone for patients with single brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR33">33</A></CITE>].=20 Once again, a level 1 recommendation reflecting a survival advantage in = this=20 setting for single-dose SRS + WBRT would only have external = validity=20 for patients with a KPS ≥ 70. </P> <P class=3D"">Whether or not a survival advantage might also exist for = patients=20 with ≥2 brain metastases remains controversial. Local tumor = control is often=20 assumed to dictate survival in a disease where 50% of patients die a=20 neurological death with WBRT alone. It can be argued that one of the two = RCTs=20 was affected by excessive bilateral cross over (especially in the 2=963 = tumor=20 patient group) confounding the intent-to-treat survival analysis for = patients=20 with 2=963 tumors, while the second RCT, using local control as the = primary=20 endpoint, was stopped at too low a power to statistically prove a = survival=20 advantage in patients with 1=964 brain metastases. Certainly, the one = class II=20 evidence study that includes patients with 1=966 metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 as well as the single class III evidence study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>]=20 consistently support a significant survival advantage for single-dose=20 SRS + WBRT in patients with multiple metastatic brain tumors.=20 Nevertheless, a survival advantage for patients with 2=964 tumors has = yet to be=20 proven at the class I evidence level, and at most a qualified level 2=20 recommendation can be supported. </P> <P class=3D"">One class II study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 and one class III study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR34">34</A></CITE>],=20 each found a survival advantage for SRS + WBRT vs. WBRT alone = for=20 patients with a KPS < 70, irrespective of brain tumor = number, so=20 long as all tumors were treated. The four arm retrospective cohort study = by Wang=20 et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>]=20 included patients with 1=966 brain metastases and KPS scores of 40=9690. = Unfortunately the KPS score distributions were not stratified by = treatment group=20 for comparison purposes. The Sanghavi et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR37">37</A></CITE>]=20 retrospective cohort study compared against the RTOG database and = stratified by=20 RPA classification is a much better designed study, but only rises to = the class=20 III evidence level. At most, the evidence supports a qualified level 3=20 recommendation regarding a survival advantage for SRS + WBRT = over WBRT=20 alone for patients with a KPS < 70. </P></DIV> <DIV class=3D""><A name=3DSec21></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy plus stereotactic radiosurgery</DIV> <P class=3D"">One RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>],=20 one prospective cohort study (class II evidence) [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>],=20 and eight of 10 retrospective cohort studies (class II evidence) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 support equivalent survival results for single-dose SRS alone vs.=20 WBRT + single-dose SRS, and one study restricted to breast = cancer=20 suggested a survival advantage for the single-dose SRS alone strategy = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>].=20 Only one retrospective cohort study showed a survival result favoring=20 WBRT + single-dose SRS, and this study was unusual in that it = only=20 included patients who had already survived >1 year since initial = treatment [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 </P> <P class=3D"">Regarding local recurrence risk, the RCT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>]=20 as well as 1/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>]=20 demonstrated that a single-dose SRS alone strategy led to a higher risk = of local=20 recurrence at the treated site compared with = WBRT + single-dose SRS. A=20 third study (second retrospective cohort study) reported an increased=20 1 year local recurrence rate (22 vs. 6%) but did not report = statistical=20 analysis [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>].=20 In contrast, the prospective cohort study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 as well as 6/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR43">43</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR46">46</A></CITE>]=20 showed no significant difference in local recurrence risk at the treated = site=20 between the two treatment strategies. Clearly there exists conflicting = data=20 regarding the risk of local recurrence at the treated site if = single-dose SRS is=20 utilized in isolation. This conflicting evidence suggests that further = study may=20 be needed to define optimal dose prescription and/or dose rate for = isolated SRS=20 as opposed to SRS performed in the setting of an additive WBRT dose. = </P> <P class=3D"">Three class I studies have demonstrated that WBRT lowers = the risk of=20 distant recurrence compared to local tumor therapies (SRS or surgical = resection)=20 used in isolation [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>].=20 There is, however, disagreement among class I and II studies regarding = the risk=20 of distant recurrence outside the treatment volume if single-dose SRS is = used in=20 isolation as opposed to WBRT + single-dose SRS. The RCT = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR38">38</A></CITE>],=20 as well as 4/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR40">40</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR44">44</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR45">45</A></CITE>],=20 demonstrated a significantly increased risk of either distant brain or = overall=20 brain recurrence when single-dose SRS is utilized in isolation and no = advantage=20 to SRS alone when assessing neurocognitive sequelae from radiation. The=20 prospective cohort study [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>]=20 as well as 2/10 retrospective cohort studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR47">47</A></CITE>]=20 did not assess the distant recurrence rate. Four of 10 retrospective = cohort=20 studies, however, revealed no significant difference in the distant = recurrence=20 rate between the two treatment strategies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR43">43</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR46">46</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR48">48</A></CITE>].=20 Given the above results, prudence warrants regular careful surveillance = at=20 2=963 month intervals with neuro-imaging if single-dose SRS is = utilized in=20 isolation. </P> <P class=3D"">An area that has not been fully studied to date includes = the=20 potential neuropsychological effects of adding WBRT to a SRS treatment = regimen=20 vs. the potential adverse neurocognitive effects of a potentially = greater risk=20 of recurrence outside the SRS site. Assessing functional status outcomes = using=20 standard functional scores tends to be insensitive to subtle = neurocognitive=20 effects. Even the MMSE is likely to be too crude a measure to assess the = neurocognitive parameters of interest to physicians and patients. Thus, = a=20 careful surveillance imaging strategy, if SRS is utilized in isolation, = should=20 be validated for both efficacy and for preserving neurocognitive = function. While=20 outside the specific search criteria for this chapter, limited evidence = to date=20 suggests that tumor recurrence is also associated with neurocognitive = decline=20 and thus may be taken into consideration when deciding to forego = up-front WBRT.=20 The potential differential neurocognitive consequences between these two = therapeutic choices (SRS alone vs. SRS + WBRT) have not been = well=20 studied and remain uncertain, even if a careful surveillance strategy is = implemented when SRS is used in isolation. </P></DIV> <DIV class=3D""><A name=3DSec22></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus whole brain = radiotherapy alone</DIV> <P class=3D"">The four class II evidence studies evaluating this = comparison all=20 demonstrated a statistically significant survival advantage for = single-dose SRS=20 alone compared with WBRT alone for patients with either single or = multiple brain=20 tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR50">50</A></CITE>].=20 However, one study was confounded by the inclusion of SCLC patients who = are=20 normally excluded from solid metastatic brain tumor analysis, = particularly in a=20 study in which WBRT is not included in one of the arms [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR35">35</A></CITE>].=20 A second study included a very small number of patients and was limited = by=20 selective rare histology (epithelial ovarian cancer only), and poor = intergroup=20 comparative analysis [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR49">49</A></CITE>].=20 Consistent with these results, one class III evidence study showed a = significant=20 survival advantage for single-dose SRS alone for RPA class I and II, but = not RPA=20 class III patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR52">52</A></CITE>].=20 Only one class III evidence study showed similar survival results for = both=20 treatment strategies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>].=20 While different studies evaluated patients with differing numbers of = brain=20 metastases, all studies included patients with up to three metastatic = brain=20 tumors. Given the relative paucity and weakness of the data, and despite = relatively consistent results, only a level 3 recommendation is = warranted.=20 </P></DIV> <DIV class=3D""><A name=3DSec23></A> <DIV class=3DHeading3>Stereotactic radiosurgery plus WBRT versus = resection plus=20 WBRT</DIV> <P class=3D"">Of the four retrospective cohort trials evaluating this = comparison,=20 three demonstrated no significant survival differences between the two=20 strategies [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>].=20 Of these, two showed a trend favoring single-dose SRS + WBRT = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR54">54</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR56">56</A></CITE>]=20 and one a trend favoring resection + WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR55">55</A></CITE>].=20 Only one of the studies demonstrated a significant survival advantage = for=20 resection + WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR51">51</A></CITE>].=20 This study reported SRS + WBRT results far worse than those = reported=20 by most studies using this strategy, both in terms of per survival = results as=20 well as excessive therapeutic toxicity and had poor enough internal = validity=20 that our writing group favored down-grading it from class II to class = III=20 evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR53">53</A></CITE>].=20 As further outlined and discussed in the surgical resection practice = guideline=20 of this series for brain metastases, these results suggest equivalence = in=20 survival results and a level 2 recommendation is consistent between the = two=20 guideline papers. </P></DIV> <DIV class=3D""><A name=3DSec24></A> <DIV class=3DHeading3>Stereotactic radiosurgery alone versus resection = plus=20 WBRT</DIV> <P class=3D"">One class I evidence study evaluating this comparison = revealed no=20 significant difference in functional performance outcome, neurological = death=20 outcome or median survival for patients with single brain metastases = [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR57">57</A></CITE>].=20 However, this study was closed prematurely with only 25% patient accrual = for a=20 study originally designed to detect a 15% difference in survival between = the two=20 groups. The revised statistical power calculation based on actual = accrual data=20 was designed to detect a survival difference of 38% or more in favor of = surgery=20 with 80% power (in accordance with a scenario retrospectively described = by=20 Bindal et al. in 1996). The actual sample size was large enough to = reject=20 the Bindal hypothesis concerning the overwhelming impact of surgery and = in fact,=20 revealed no significant difference between the two groups. </P> <P class=3D"">Of the three class II evidence studies evaluating this = comparison,=20 two revealed no significant difference in median survival for patients = with 1=963=20 brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 One suggested a trend favoring single-dose SRS alone for patients with = 1=963=20 tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR59">59</A></CITE>],=20 while the other suggested a trend favoring resection + WBRT = for=20 patients with single metastatic tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 The third study demonstrating a significant survival advantage for=20 resection + WBRT or local RT was confounded by poor = comparability=20 among patient treatment arms with the SRS alone arm containing more than = twice=20 the percentage of multiple metastatic brain tumor patients than the=20 resection + RT arm [<CITE><A=20 href=3D"http://www.springerlink.com/content/7w84227x88442213/fulltext.htm= l#CR60">60</A></CITE>].=20 </P> <P class=3D"">While the result for this comparison is one of the most = eagerly=20 anticipated in neuro-oncology, the current power flaws for the only = class I=20 evidence study, as well as the relative paucity, weakness, and = conflicting=20 results among other published evidence at most supports a level 3 = recommendation=20 for SRS in lieu of resection + WBRT. </P></DIV> <DIV class=3D""><A name=3DSec25></A> <DIV class=3DHeading3>Other comparisons</DIV> <DIV class=3DPara> <DIV class=3D"">The absent and/or severely limited evidence (number as = well as=20 quality of studies) so far published in peer review literature does not = yet=20 support any clinical practice parameter guideline recommendations = regarding:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>The effectiveness of resection + single-dose SRS vs.=20 resection + WBRT for patients with one or more solid = brain=20 metastases.</TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>The effectiveness of substituting 2=965 dose SRS, or even 6=969 = dose FSR,=20 for single-dose SRS evaluated in the comparisons above and = reflected in=20 the clinical practice parameter guideline recommendations. = </TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>The effectiveness of substituting local RT for WBRT in the = comparisons=20 above and reflected in the clinical practice parameter guideline=20 recommendations. </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec26></A> <DIV class=3DHeading3>Key issues for further investigation</DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>The potential survival advantage of single-dose = SRS + WBRT=20 for patients with ≥2 metastatic brain tumors <3 cm = in diameter=20 remains controversial and warrants further investigation with a = RCT=20 designed for sufficient statistical power for these patients with = median=20 survival as the primary endpoint. </TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>The potential survival advantage of single-dose = SRS + WBRT=20 for patients with a KPS < 70 warrants further = investigation=20 in the form of a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>The local control advantage of single-dose SRS for patients with = ≥4=20 metastatic brain tumors and a KPS ≥ 70 warrants = further=20 investigation in the form of a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>The optimal dose and/or dose rate for single-dose SRS utilized = in=20 isolation for treating metastatic brain tumors in order to ensure=20 equivalent local recurrence rates compared with current single = dose=20 SRS + WBRT doses warrants further study. </TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>The neurocognitive effects of SRS alone with careful = neuroimaging=20 follow-up leading to potential salvage SRS if recurrence develops, = vs.=20 SRS + WBRT, warrants further study with appropriate = validated=20 neurocognitive instruments and endpoints. </TD></TR> <TR vAlign=3Dtop> <TD>6. </TD> <TD>Based on current evidence classifications, single-dose=20 SRS + WBRT vs. resection + WBRT warrants = investigation=20 in the form of a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>7. </TD> <TD>Single-dose SRS alone vs. resection + WBRT warrants = further=20 investigation in the form of either a prospective cohort study or = a RCT.=20 </TD></TR> <TR vAlign=3Dtop> <TD>8. </TD> <TD>Resection + single-dose SRS vs. = resection + WBRT=20 warrants further investigation in the form of either a prospective = cohort=20 study or a RCT. </TD></TR> <TR vAlign=3Dtop> <TD>9. </TD> <TD>2=965 dose SRS is relatively unproven in any of the comparison = paradigms=20 discussed in this paper. Clinical trials of 2=963 dose SRS vs. = single-dose=20 SRS are needed for all treatment comparisons outlined in this = paper in=20 either the form of prospective cohort studies or RCTs. </TD></TR> <TR vAlign=3Dtop> <TD>10. </TD> <TD>The effectiveness of local RT is relatively unproven compared = with=20 WBRT in any of the comparison paradigms discussed in this paper. = Clinical=20 trials of local RT vs. WBRT are most needed for settings of = limited CNS=20 disease where treatment strategies are designed to maximize local = control=20 (e.g., SRS + local RT vs. SRS + WBRT or=20 resection + local RT vs. resection + WBRT).=20 </TD></TR></TBODY></TABLE></DIV></DIV> <DIV class=3DPara> <DIV class=3D"">The following is a list of major ongoing randomized = trials=20 pertaining to the use of stereotactic radiosurgery that evaluate = treatment=20 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>Randomized trial comparing radiosurgery with vs without whole = brain=20 radiotherapy=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A phase III prospective = randomized=20 trial comparing radiosurgery with versus without whole brain = radiotherapy=20 for 1=963 newly diagnosed brain 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> NCT00548756=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Eric L. Chang, MD, = U.T.M.D.=20 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>2. </TD> <TD>Stereotactic radiation therapy with or without whole-brain = radiation=20 therapy in treating patients with brain metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Phase III randomized trial = of the=20 role of whole brain radiation therapy in addition to radiosurgery = in=20 patients with one to three cerebral 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> NCT00377156=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Paul D. Brown, MD Mayo = Clinic</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Kurt A. Jaeckle, MD Mayo = Clinic</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Richard L. Deming, MD Mercy = Therapeutic=20 Radiology Associates, PC at Mercy Medical Center - Des = Moines</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Elana Farace, PhD Milton S. Hershey = Medical=20 Center</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Bruce Pollock, MD Mayo = Clinic</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Anthony Asher, MD, FACS Carolina = Neurosurgery=20 and Spine Associates</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Investigator: Fred G. Barker, MD Massachusetts = General=20 Hospital</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Larry Kleinberg, MD Sidney Kimmel = Comprehensive=20 Cancer Center</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Study Chair: Anthony Asher, MD, FACS Carolina = Neurosurgery=20 and Spine Associates</DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States and Canada (38 = locations)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">North Central Cancer Treatment Group</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">National Cancer Institute (NCI)</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">American College of Surgeons</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Eastern Cooperative Oncology Group</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Radiation Therapy Oncology = Group</DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>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>4. </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>5. </TD> <TD>A trial of postoperative whole brain radiation therapy vs. = 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> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Japan Clinical Oncology Group</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Japanese Ministry of Health, Labor and=20 Welfare</DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>6. </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""><B>Principal Investigator:</B> Daniel Roos, = FRANZCR, Royal=20 Adelaide 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>7. </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> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Rolf-Peter Mueller, MD Medizinische = Universitaetsklinik I at=20 the University of Cologne</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Riccardo Soffietti, MD Universita Degli Studi di=20 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 = &=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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