10.1007/s11060-009-0058-3</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/s11060-009-0058-3</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of emerging and = investigational=20 therapies for metastatic brain tumors: a systematic review and = evidence-based=20 clinical practice guideline of selected topics </DIV> <P class=3DAuthorGroup>Jeffrey J. Olson<SUP>1</SUP>,=20 Nina A. Paleologos<SUP>2</SUP>,=20 Laurie E. Gaspar<SUP>3</SUP>, = Paula D. Robinson<SUP>4</SUP>,=20 Rachel E. Morris<SUP>4</SUP>, Mario Ammirati<SUP>5</SUP>, = David W. Andrews<SUP>6</SUP>, = Anthony L. Asher<SUP>7</SUP>,=20 Stuart H. Burri<SUP>8</SUP>, = Charles S. Cobbs<SUP>9</SUP>,=20 Douglas Kondziolka<SUP>10</SUP>, = Mark E. Linskey<SUP>11</SUP>,=20 Jay S. Loeffler<SUP>12</SUP>, = Michael McDermott<SUP>13</SUP>,=20 Minesh P. Mehta<SUP>14</SUP>, Tom Mikkelsen<SUP>15</SUP>, = Roy A. Patchell<SUP>16</SUP>, = Timothy C. Ryken<SUP>17</SUP>=20 and Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#ContactOfAuthor19"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/vw55868761322267/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, 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=3DAff2></A>(2) </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=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = University=20 of Colorado-Denver, Denver, CO, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>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=3DAff5></A>(5) </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=3DAff6></A>(6) </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=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Carolina=20 Neurosurgery and Spine Associates, Charlotte, NC,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = Carolinas=20 Medical Center, Charlotte, NC, = 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 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=3DAff10></A>(10) </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=3DAff11></A>(11) </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=3DAff12></A>(12) </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=3DAff13></A>(13) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff14></A>(14) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Human Oncology, = University of=20 Wisconsin School of Public Health and Medicine, Madison, WI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Henry Ford = Health=20 System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff16></A>(16) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff17></A>(17) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Iowa Spine = and=20 Brain Institute, Iowa City, IA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff18></A>(18) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Henry Ford = Health=20 System, Hermelin Brain Tumor Center, 2799 West Grand Blvd, K-11, = Detroit,=20 MI 48202, USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor19></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/vw55868761322267/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>8 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B> </SPAN>What evidence is = available=20 regarding the emerging and investigational therapies for the treatment = of=20 metastatic brain tumors?=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 brain=20 metastases.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>New radiation sensitizers</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> A subgroup analysis of a large = prospective=20 randomized controlled trial (RCT) suggested a prolongation of time to=20 neurological progression with the early use of motexafin-gadolinium = (MGd).=20 Nonetheless this was not borne out in the overall study population and = therefore=20 an unequivocal recommendation to use the currently available radiation=20 sensitizers, motexafin-gadolinium and efaproxiral (RSR 13) cannot be = provided.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Interstitial modalities</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">There is no evidence to support the routine use of new = or existing=20 interstitial radiation, interstitial chemotherapy and or other = interstitial=20 modalities outside of approved clinical trials. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>New chemotherapeutic agents</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Treatment of melanoma brain metastases = with whole=20 brain radiation therapy and temozolomide is reasonable based on one = class II=20 study. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Depending on individual circumstances = there may be=20 patients who benefit from the use of temozolomide or fotemustine in the = therapy=20 of their brain metastases. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Molecular targeted agents</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> The use of epidermal growth factor = receptor=20 inhibitors may be of use in the management of brain metastases from = non-small=20 cell lung carcinoma. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Radiation sensitizers - Interstitial=20 modalities - New chemotherapeutic agents - Molecular = targeted agents - Anti-angiogenesis = agents - Systematic=20 review - Practice guideline </P> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">As can be gleaned by the data collected and the questions = assessed=20 in the other papers in this guideline series, uniformly successful = control of=20 brain metastases has not been achieved. Even in those selected cases of=20 outstanding control, toxicity from the treatment itself can result in an = overall=20 decrement in the person=92s level of function. Fortunately there is = research=20 proceeding on a number of fronts to improve this situation. To provide = some=20 insight into these investigative areas, modalities that have reached the = point=20 of assessment by clinical trials warrant critical review. </P> <P class=3D"">The objectives of this paper are to assess both = comparative and=20 non-comparative studies of the following therapies that are still in the = investigational stage (i.e., not currently available outside of clinical = trials). This will include (1) the radiation sensitizers = motexafin-gadolinium=20 and RSR 13, (2) local modalities placed at the time of surgical excision = including local irradiation with the balloon-based brachytherapy,=20 stereotactically placed radiation sources, and local chemotherapy with=20 BCNU-impregnated polymers, (3) the role of the chemotherapeutic agents=20 temozolomide and fotemustine, and (4) the molecular targeted agents = against=20 epidermal growth factor or angiogenic receptors. </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. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR1">1</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"">For literature to be included for consideration in = creation of the=20 guidelines related to this question, it needed to meet the following = criteria:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Include patients with brain metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Arise from fully-published primary studies with a publication = date of=20 1990 forward or abstracts from the 2006=962008 meetings of AANS, = CNS, SNO,=20 ASTRO, ASCO and the AANS/CNS joint section on tumors satellite = symposiums=20 (all study designs for primary data collection were included; = e.g.,=20 randomized controlled trials, non-randomized trials, cohort = studies,=20 case=96control studies, or case series). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Evaluation of one or more or the following modalities was = necessary:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Radiation sensitizers:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Motexafin-gadolinium</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Efaproxiral (RSR=20 13)</TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Local modalities placed at the time of surgical excision or = biopsy:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Local irradiation=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Balloon tipped catheter placement</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Interstitial radiosurgery or brachytherapy (without=20 hyperthermia)</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Local chemotherapy to the resection=20 cavity</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>New chemotherapeutic agents: temozolomide or fotemustine=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Molecular targeted agents: Gefitinib (ZD1839)</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Anti-angiogenesis agents: Bevacizumab=20 (Avastin)</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>The number of study participants with brain metastases needed to = be=20 >5 per study arm for at least two of the study arms for = comparative=20 studies and >5 overall for non-comparative studies. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>The following criteria was applied to full-length papers, but = not=20 meeting abstracts: For studies evaluating interventions = exclusively in=20 patients with brain metastases, the baseline characteristics of = study=20 participants needed to be provided by treatment group for = comparative=20 designs and overall for non-comparative studies. For studies with = mixed=20 populations (i.e., includes participants with conditions other = than brain=20 metastases), baseline characteristics needed to be provided for = the=20 sub-group of participants with brain metastases, and stratified by = treatment group for comparative studies.=20 </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Study selection and quality assessment</DIV> <P class=3D"">Two independent reviewers evaluated citations using a = priori=20 criteria for relevance and documented decisions in standardized forms. = Cases of=20 disagreement were resolved by a third reviewer. The same methodology was = used=20 for full text screening of potentially relevant papers. Studies which = met the=20 eligibility criteria were data extracted by one reviewer and the = extracted=20 information was checked by a second reviewer. The PEDro scale [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR3">3</A></CITE>]=20 was used to rate the quality of randomized trials. The quality of = comparative=20 studies using non-randomized designs was evaluated using eight items = selected=20 and modified from existing scales. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper accompanying this = guideline=20 series. </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of questions to be answered regarding the practice=20 guidelines on the management of brain metastases based on a systematic = review of=20 the literature conducted in collaboration with methodologists at the = McMaster=20 University Evidence-based Practice Center. </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">Overall, 59 publications (53 primary studies and 6 = companion=20 papers) met the eligibility criteria for use in the discussion of the = scientific=20 foundation of this guideline (Fig. <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Fig1">1</A>).=20 A summary of the class of evidence of all the primary studies discussed = in this=20 scientific foundation are presented in Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab1">1</A>.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_58_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/vw55868761322267/MediaObjects/= 11060_2009_58_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> <A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>The = evidence class=20 provided by the included primary studies </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Description of evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Class of evidence provided by included primary=20 studies</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">New radiation sensitizers: motexafin-gadolinium and=20 efaproxiral</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class I</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">3 RCTs: Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>],=20 Suh [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR5">5</A></CITE>],=20 Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">1 Prospective cohort study with historical controls: = Shaw=20 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1 Prospective single arm study: Carde [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">Interstitial modalities</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class I</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">1 Retrospective cohort study: Ostertag [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">3 Prospective single arm studies:</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Ewend [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>],=20 Rogers [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>],=20 Nakagawa [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">7 Case series: Alesch [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>],=20 Bernstein [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>],=20 Bogart [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>],=20 Dagnew [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>],=20 Schulder [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>],=20 Curry [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>],=20 Nakamura [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">New chemotherapeutic agents: Temozolomide or=20 fotemustine</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Class I</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">1 RCT: Mornex [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2 Randomized phase II trials: Antonadou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>],=20 Verger [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">2 Retrospective cohort studies: Conill [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>],=20 Panagiotou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">22 Prospective single arm studies: Abrey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>],=20 Addeo [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>],=20 Agarwala [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>],=20 Caraglia [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>],=20 Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>],=20 Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>],=20 Cortot [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>],=20 Giorgio [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>],=20 Hwu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>],=20 Iwamoto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>],=20 Janinis [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR48">48</A></CITE>],=20 Kouvaris [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>],=20 Krown [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>],=20 Larkin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>],=20 Margolin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>],=20 Omuro [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>],=20 Rivera [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>],=20 Schadendorf [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>],=20 Brocker [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>],=20 Chang [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>],=20 Cotto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR62">62</A></CITE>],=20 Jacquilat [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2 Case series: Hofmann [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR45">45</A></CITE>],=20 Ulrich [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2 Sub-group analyses of prospective studies: = Bafaloukos=20 (2006),</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Boogerd [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">Molecular targeted agent: Gefitinib (ZD = 1839)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class I</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">3 Prospective single arm studies: Ceresoli [<CITE><A = = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR71">71</A></CITE>],=20 Chiu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR72">72</A></CITE>],=20 Wu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">3 Case series: Hotta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>],=20 Namba [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR69">69</A></CITE>],=20 Shimato [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">70</A></CITE>]=20 </P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D"">Fully published papers. Conference proceeding abstracts = not=20 included</DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>New radiation sensitizers</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided five unique studies = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>]=20 and five companion papers [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR9">9</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR13">13</A></CITE>]=20 that met the criteria for support of guidelines recommendations = regarding the=20 use of new radiation sensitizers in the management of brain metastases=20 (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab2">2</A>).<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Summary = of primary=20 radiation sensitizer 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/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"">Tumor response</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"">Motexafin-gadolinium</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Carde [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase Ib/II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + MGd (phase Ib = <I>n</I> =3D 39; phase=20 II <I>n</I> =3D 22) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">4.7 months (Phase 1b + phase = II)</P></TD> <TD align=3Dleft> <P class=3D"">Radiographic response in brain:</P> <P class=3D"">Phase Ib (23 assessable pts):</P> <P class=3D"">CR 1/23, PR 13/23, SD 8/23, PD 1/23</P> <P class=3D"">Phase II (18 assessable pts):</P> <P class=3D"">CR 0/18, PR 13/18, SD 4/18, PD 1/18</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>]=20 (2003) </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 208) </P> <P class=3D"">G2: WBRT + MGd = (<I>n</I> =3D 193) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.9 months</P> <P class=3D"">G2: 5.2 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain (CR or PR):</P> <P class=3D"">G1: 50.7%</P> <P class=3D"">G2: 46.3% (<I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Median time to neurologic progression (by ERC):</P> <P class=3D"">G1: 8.3 months</P> <P class=3D"">G2 9.5 months (log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">Median time to neurologic progression (by = investigators):</P> <P class=3D"">G1: 3.8 months</P> <P class=3D"">G2 4.3 months (log-rank; = <I>p</I> =3D 0.018)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>]=20 (2008) </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 275) </P> <P class=3D"">G2: WBRT + MGd = (<I>n</I> =3D 279) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 5.8 months</P> <P class=3D"">G2: 5.1 months (log-rank; = <I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Interval to neurologic progression:</P> <P class=3D"">G1: 10.0 months</P> <P class=3D"">G2: 15.4 months (Neurologic progression curves: = stratified log-rank; <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Efaproxiral (RSR 13)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shaw [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT [historical controls]</P> <P class=3D"">(<I>n</I> =3D 1070) </P> <P class=3D"">G2: WBRT + efaproxiral</P> <P class=3D"">(<I>n</I> =3D 57 RPA class II) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.1 months</P> <P class=3D"">G2: 6.4 months (Survival curves: log-rank;=20 <I>p</I> =3D 0.0174) </P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">G1: Not reported</P> <P class=3D"">G2: CR 7/57, PR 13/57, SD 21/57</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Suh [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR5">5</A></CITE>]=20 (2006) </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 + supplemental O<SUB>2</SUB>=20 (<I>n</I> =3D 250) </P> <P class=3D"">G2: WBRT + supplemental=20 O<SUB>2</SUB> + efaproxiral (<I>n</I> =3D 265) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.4 months</P> <P class=3D"">G2: 5.4</P> <P class=3D"">months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">NSCLC/breast cancer sub-group:</P> <P class=3D"">G1: 4.4 months</P> <P class=3D"">G2: 6.0 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain (CR or PR):</P> <P class=3D"">G1: 96/250 (38%)</P> <P class=3D"">G2: 121/265 (46%) (<I>p</I> =3D NS) </P> <P class=3D"">Response rate in NSCLC/breast cancer sub-group:</P> <P class=3D"">G1: 41%</P> <P class=3D"">G2: 54% (<I>p</I> =3D 0.01) </P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival:</P> <P class=3D"">G1: 3.5 months</P> <P class=3D"">G2: 4.0 month (log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">Median progression-free survival in NSCLC/breast = cancer=20 sub-group:</P> <P class=3D"">G1: 3.7 months</P> <P class=3D"">G2: 4.8 month (log-rank; = <I>p</I> =3D NS)=20 </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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>LR</I> Local recurrence at original site in = brain,=20 <I>MGd</I> Motexafin-gadolinium, <I>NR</I> Not reported, <I>NS</I> Not=20 significant, <I>NSCLC</I> Non-small cell lung cancer, <I>OR</I> = Objective=20 response, <I>PR</I> Partial response, <I>Pts</I> Patients, <I>RCT</I> = Randomized=20 control trial, <I>SRS</I> Stereotactic radiosurgery, <I>TMZ</I> = Temozolomide,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV></DIV></DIV></DIV> <P class=3D"">Many radiation sensitizers have been investigated to try = to increase=20 the effectiveness of whole-brain radiation therapy (WBRT). Two recent = radiation=20 sensitizers that have been extensively evaluated are motexafin = gadolinium and=20 efaproxiral. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Motexafin gadolinium</DIV> <P class=3D"">Motexafin gadolinium (MGd) is a metallotexaphrin that = localizes=20 within tumors in greater concentration than in normal tissues. This = agent is=20 detectable by magnetic resonance imaging (MRI) because it contains the=20 paramagnetic metal ion, gadolinium. Its exact mechanism of action is not = known=20 although it is known to be involved with electron scavenging. It may act = as both=20 a radiation sensitizer and modifier. </P> <P class=3D"">There is one prospective single arm study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>]=20 (class III evidence) and two randomized controlled studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>]=20 (class I evidence) evaluating MGd as a radiation sensitizer. Carde et = al.=20 published a prospective single arm phase Ib/II study which established = MGd=20 5 mg/kg given intravenously daily as the recommended best tolerated = dose=20 when combined with 30 Gy WBRT given in 10 fractions of 3 Gy. = This=20 yielded class III evidence regarding the feasibility and potential = efficacy of=20 MGd [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>].=20 </P> <P class=3D"">A subsequent randomized controlled study in 401 patients = with brain=20 metastases of various histologies, comparing WBRT alone versus WBRT with = motexafin gadolinium failed to show any significant difference in median = survival or tumor response [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>].=20 However, the median time to neurologic progression as determined by the=20 investigators was increased by 0.5 months = (<I>p</I> =3D 0.018) for=20 the group that received motexafin gadolinium. This effect was attributed = predominantly to the lung cancer stratum. Patients were stratified by = histology=20 (lung, breast or other) and a subset analysis revealed that the time to=20 neurological progression favored the MGd and WBRT arm for patients with = lung=20 cancer (median 5.5 months for MGd v 3.7 months for WBRT alone, = <I>p</I> =3D 0.025), but no difference was seen in the other = strata. A=20 companion study of neurocognitive function by Meyers et al. further = suggested=20 that MGd may preserve memory and executive function and prolong time to=20 neurocognitive and neurologic progression in patients with brain = metastases from=20 lung cancer [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR9">9</A></CITE>].=20 </P> <P class=3D"">An international phase III study was therefore conducted,=20 randomizing 554 patients with non-small cell lung carcinoma (NSCLC) to = WBRT=20 alone (30 Gy in 10 fractions) or to WBRT with MGd [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>].=20 The primary endpoint of the study was time to neurologic progression. = Although=20 time to neurological progression was improved in the MGd arm, it was not = a=20 statistically significant difference unless the patients enrolled = outside of=20 North America were excluded. In a subgroup analysis of the 348 North = American=20 patients, there was a statistically significant prolongation of time to=20 neurological progression from 8.8 to 24.2 months,=20 <I>p</I> =3D 0.04. This difference in outcome between the = North American=20 patients and patients treated elsewhere was attributed to the fact that = patients=20 in North America received the study treatment sooner after the diagnosis = of the=20 brain metastases. When WBRT was initiated within three weeks of = diagnosis of the=20 brain metastases, regardless of whether the patient was treated in North = America=20 or not, time to neurological progression was significantly prolonged by = the=20 addition of MGd (<I>p</I> =3D 0.006, HR =3D 0.59). A = major=20 reason for the delay to WBRT outside of North America was the use of=20 chemotherapy. This study failed to meet its primary objective of = increasing time=20 to neurologic progression and is considered a negative study. However = the=20 subgroup analysis mentioned, though post hoc and selective in nature, = can be=20 interpreted as providing class 2 evidence. </P></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Efaproxiral</DIV> <P class=3D"">Efaproxiral, (also known as RSR13; Allos Therapeutics, = Westminster,=20 CO) is an allosteric modifier of hemoglobin. Efaproxiral binds to = hemoglobin,=20 causing a change in its conformational structure, leading to a reduction = in=20 hemoglobin oxygen binding affinity. This leads to an increased release = of oxygen=20 into tissue, enhancing tumor oxygenation leading to radiation = sensitization.=20 Shaw et al. completed a phase II study in which 57 patients with brain=20 metastases received WBRT (30 Gy in 10 fractions of 3 Gy) with = daily=20 efaproxiral 50=96100 mg/kg. This yielded class III data showing = median=20 survival was 6.4 months which compared favorably to the Radiation = Therapy=20 Oncology Group=92s (RTOG) historical control patients (4.1 months) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>].=20 </P> <P class=3D"">This prompted a large phase III study of WBRT alone versus = WBRT with=20 efaproxiral in 515 patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR5">5</A></CITE>].=20 This study failed to reveal a significant difference in median survival, = tumor=20 response or median time to recurrence/progression with the addition of=20 efaproxiral although it prompted a confirmatory trial in patients with = brain=20 metastases related to breast cancer. The investigators found that = patients with=20 brain metastases related to breast cancer were more likely to receive at = least 7=20 of the planned 10 fractions of efaproxiral and were more likely to have = an=20 increased concentration of efaproxiral in red blood cells as compared to = patients with brain metastases due to other primary cancers such as lung = cancer=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR12">12</A></CITE>].=20 However, the confirmatory phase III study in breast cancer patients of = WBRT with=20 efaproxiral versus WBRT alone failed to demonstrate an improvement in = overall=20 survival or any other prespecified endpoint [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR14">14</A></CITE>].=20 </P> <P class=3D"">In summary, there is class I evidence that motexafin = gadolinium=20 (MGd) given daily during WBRT does not increase survival over survival = following=20 WBRT alone. Additionally, there is also class I evidence that = efaproxiral given=20 daily during WBRT does not increase survival over survival following = WBRT alone.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec12></A> <HR> <DIV class=3Dheading2>Radiation sensitizers summary</DIV> <P class=3D"">Considerable effort has been put into the development of = motexafin=20 gadolinium and efaproxiral yielding class I data supporting the = conclusion that=20 these agents do not improve the therapy of brain metastases. This is not = to say=20 that radiation sensitizers are without merit. The lessons learned in the = studies=20 reviewed here provide direction for further investigation and = encouraging=20 patient participation in such studies is warranted. </P></DIV> <DIV class=3D""><A name=3DSec13></A> <HR> <DIV class=3Dheading2>Interstitial modalities</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided 11 unique studies = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 and one companion study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR26">26</A></CITE>]=20 that met the criteria for support of guidelines recommendations = regarding the=20 use of interstitial modalities in the management of brain metastases=20 (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab3">3</A>).=20 In this discussion brachytherapy is defined as therapy placed inside of = or next=20 to the area being treated. Interstitial radiosurgery is defined here as=20 brachytherapy in which the therapy specifically consists of radiation.<A = name=3DTab3></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 3 </SPAN>Summary = of=20 interstitial modalities 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/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"">Tumor control</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"">Brachytherapy =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ostertag [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 (1995) </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: Temporary <SUP>125</SUP>Iseeds + WBRT=20 (<I>n</I> =3D 38) </P> <P class=3D"">G2: Temporary 125I seeds (<I>n</I> =3D 34) = </P> <P class=3D"">G3: Temporary <SUP>125</SUP>I seeds for recurrent BM = (<I>n</I> =3D 21) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 17 months</P> <P class=3D"">G2: 15 months</P> <P class=3D"">G3: 6 months</P> <P class=3D"">(Survival curves G1 vs. G2: Lee-Desu statistic;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR by treatment group</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Alesch [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Temporary <SUP>125</SUP>I seeds = (<I>n</I> =3D 19)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain (by CT scan):</P> <P class=3D"">Marked reduction 5/19</P> <P class=3D"">Slight reduction 11/19</P> <P class=3D"">Unchanged 2/19</P> <P class=3D"">Not evaluable 1/19</P> <P class=3D""># of pts with LR: 1/19</P> <P class=3D""># of pts with DR: 1/19</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bernstein [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Temporary high-activity <SUP>125</SUP>I seeds=20 (<I>n</I> =3D 10) </P></TD> <TD align=3Dleft> <P class=3D"">Single locally recurrent BM</P></TD> <TD align=3Dleft> <P class=3D"">46 weeks</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"">Surgery + brachytherapy</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bogart [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + permanent l<SUP>125</SUP>I seeds = (<I>n</I> =3D 15) </P></TD> <TD align=3Dleft> <P class=3D"">Single newly diagnosed BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">14 months</P></TD> <TD align=3Dleft> <P class=3D"">LR only: 2/15</P> <P class=3D"">DR only: 2/15</P> <P class=3D"">LR + DR: 1/15</P></TD> <TD align=3Dleft> <P class=3D"">Median time to BM recurrence: = 9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Dagnew [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + permanent <SUP>125</SUP>I seeds=20 (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft> <P class=3D"">Single newly diagnosed</P> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">17.8 months</P></TD> <TD align=3Dleft> <P class=3D""># of pts with local control: 25/26</P> <P class=3D""># of pts with DR: 10/26 (38%)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rogers [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm Phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + GliaSite balloon catheter with=20 <SUP>125</SUP>I (<I>n</I> =3D 54) </P></TD> <TD align=3Dleft> <P class=3D"">Single newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">40 weeks</P></TD> <TD align=3Dleft> <P class=3D"">1 yr local control rate: 79%</P> <P class=3D"">1 yr distant brain control rate: 50%</P></TD> <TD align=3Dleft> <P class=3D"">Median time to distant brain recurrence:=20 54 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schulder [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>]=20 (1997) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + permanent <SUP>125</SUP>I seeds=20 (<I>n</I> =3D 13) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">7.6 months overall;</P> <P class=3D"">9 months if exclude two post-op deaths</P></TD> <TD align=3Dleft> <P class=3D""># of pts with local control: 9/11</P> <P class=3D""># of pts with DR: 7/11</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Surgery + local=20 chemotherapy =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ewend [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + carmustine polymer = wafers + WBRT=20 (<I>n</I> =3D 25) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed single BM</P></TD> <TD align=3Dleft> <P class=3D"">33 weeks</P></TD> <TD align=3Dleft> <P class=3D""># of pts with LR: 0/25 (0%)</P> <P class=3D""># of pts with DR: 4/25 (16%)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Nakagawa [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + FdUrd intracavitary chemotherapy = (<I>n</I> =3D 6 for BM sub-group) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain:</P> <P class=3D"">Complete response 3/6</P> <P class=3D"">No change 1/6</P> <P class=3D"">Progressive disease 2/6</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Interstitial radiosurgery</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Curry [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Stereotatic interstitial radiosurgery with = photon</P> <P class=3D"">Radiosurgery system (<I>n</I> =3D 60) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">8 months</P></TD> <TD align=3Dleft> <P class=3D"">Of 59 evaluable BM; 13 BM not assessable</P> <P class=3D"">Lesion with local control: 48/59 (81%)</P> <P class=3D"">Lesions with progression: 11/59 (19%)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Nakamura [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + intra-operative radiation = therapy=20 (<I>n</I> =3D 43) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">1 yr survival rate: 53%</P></TD> <TD align=3Dleft> <P class=3D""># of pts with LR: 7/43</P> <P class=3D""># of pts with DR: 7/43</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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>KPS</I> Karnofsky performance score, <I>LR</I> = Local=20 recurrence at original site in brain, <I>MGd</I> Motexafin-gadolinium, = <I>NR</I>=20 Not reported, <I>NS</I> Not significant, <I>NSCLC</I> Non-small cell = lung=20 cancer, <I>OR</I> Objective response, <I>PR</I> Partial response, = <I>Pts</I>=20 Patients, <I>RCT</I> Randomized control trial, <I>SRS</I> Stereotactic=20 radiosurgery, <I>TMZ</I> Temozolomide, <I>WBRT</I> Whole-brain radiation = therapy=20 </DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec14></A> <DIV class=3DHeading3>Brachytherapy with or without whole brain = radiation=20 therapy</DIV> <P class=3D"">One retrospective series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 looking at three cohorts and two case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>]=20 met criteria for inclusion of their data in this portion of the = guideline. </P> <DIV class=3D""><A name=3DSec15></A> <H4 class=3DSection3>Retrospective multiple cohort series</H4> <P class=3D"">In a retrospective cohort study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 of the temporary implantation of <SUP>125</SUP>I seeds for spherical = brain=20 metastases (from a variety of primary sites) 4 cm or smaller in = diameter=20 Ostertag et al. looked at three groups of patients that the authors = refer to as=20 A, B and C, respectively, with A being temporary <SUP>125</SUP>I seeds = and WBRT=20 for patients with newly diagnosed brain metastases, B being temporary=20 <SUP>125</SUP>I seeds alone in patients newly diagnosed with brain = metastases,=20 and C being temporary <SUP>125</SUP>I seeds for patients with recurrent = brain=20 metastases treated with other modalities first. The chosen dose of = interstitial=20 radiation was 60 Gy prescribed to the rim of the lesion(s). The = dose of=20 WBRT was chosen to be 40 Gy in 2 Gy daily fractions. In terms = of=20 clinical characteristics, three cases with two lesions were treated in = the first=20 group, four cases with two lesions were treated in the second group and = twelve=20 cases with two lesions were treated in the third group. The groups were = balanced=20 except for age. The median age was 55 years, 58 years, and=20 47 years, by group, respectively, with a statistically significant = younger=20 age for the third group. Median survivals for the three groups were 17, = 15 and=20 6 months, respectively. The shorter survivals in those with = recurrent and=20 longer standing disease was not considered surprising. The difference = between=20 the first two brachytherapy groups (with or without WBRT, respectively) = was not=20 significant using Lee=96Desu statistic to assess the Kaplan=96Meier = survival curves.=20 The authors state that the temporary <SUP>125</SUP>I sources utilized in = the=20 manner outlined were not associated with radiation necrosis requiring = surgery in=20 any case. They go onto advocate =93interstitial radiosurgery=94 as a = method of=20 avoiding or postponing WBRT. The properly executed retrospective = comparison of=20 the cohorts treated here yielded class II evidence. However, the numbers = treated=20 in each group are moderate in nature and no comparison to metastatic = tumors=20 treated in a more standard method is provided. Thus, a level 2 = recommendation=20 cannot be provided [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec16></A> <H4 class=3DSection3>Case series</H4> <P class=3D"">In a case series of 19 patients, Alesch et al., describe = their use=20 of temporary <SUP>125</SUP>I seeds treating metastases from a variety of = primary=20 lesions with a tumor margin dose of 60 Gy. All but one case had one = lesion.=20 A mean dose rate of 11 cGy/hour (ranging from 5 to = 22 cGy/hour) was=20 used and the mean irradiation time before explantation was 28 days = (ranging=20 from 11 to 52 days). They utilized a simplistic plan with only one = catheter=20 per lesion. The authors point out the value of biopsy at the time of = implant to=20 rule out other processes, which excluded three cases from their series. = CT was=20 the predominant modality used for imaging and response assessment, = leaving the=20 possibility of other untreated small lesions open to question. The = responses=20 were classified as marked reduction (5 cases), slight reduction (11 = cases),=20 unchanged (2 cases) and not evaluable (1 case). Marked reduction versus = slight=20 reduction was not defined further. One patient had a temporary worsening = of an=20 existing hemiparesis. No patient died from neurologic causes. No mention = of=20 symptomatic radiation necrosis is provided. As this report is a case = series it=20 meets the criteria for class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>].=20 </P> <P class=3D"">In a small series of ten cases of single brain metastases = that had=20 recurred at the same site after surgical resection and WBRT Bernstein et = al.=20 describe the use of high activity <SUP>125</SUP>I seeds used to = administer=20 70 Gy or more at periphery of the lesion at a median dose rate of=20 67 cGy/h. Nine of the cases had lung primaries. The median time to = tumor=20 recurrence was 35 weeks. Median survival was 46 weeks. = Reoperation at=20 the implant site was necessary in three cases because of symptomatic = mass=20 effect, two for radiation necrosis and one for mixed tumor and radiation = necrosis. Two early deaths occurred from pulmonary emboli. The authors = point out=20 that the cases were highly selected and conclude that a more detailed = controlled=20 and randomized study compared to other therapies is necessary to assess = the real=20 value of this mode of therapy in brain metastases. This case series with = no=20 comparative component meets the criteria to provide class III evidence = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>].=20 This and the cases series by Alesch et al. support the feasibility of = this=20 modality but do not provide evidence of comparative efficacy necessary = to more=20 strongly support its recommendation [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>].=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec17></A> <DIV class=3DHeading3>Surgery and brachytherapy</DIV> <P class=3D"">One fully published single arm phase II study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>]=20 and three case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>]=20 met criteria for inclusion of their data in this portion of the = guideline. </P> <DIV class=3D""><A name=3DSec18></A> <H4 class=3DSection3>Phase II single arm studies</H4> <P class=3D"">To look at the efficacy of the Gliasite Radiation Therapy = System=20 after surgical resection of single brain metastases Rogers et al. = designed a=20 phase II study. This system entails surgical placement of a balloon that = is=20 connected to a reservoir that is implanted subcutaneously. Liquid = containing=20 <SUP>125</SUP>I is then inserted postoperatively into the balloon by = injection=20 into the reservoir. Patients were required to have a single resected = lesion and=20 to have a Karnofsky performance score (KPS) of 70 or above. Fifty-four = cases=20 with tumors from a variety of primary sites were enrolled with a median = age of=20 60 and a median KPS of 90. The planned dose of radiation was 60 Gy = to a one=20 cm depth from the balloon surface. One year local control rate was the = primary=20 outcome assessed and was 79%. Distant brain control at the same interval = was 50%=20 with median time to development of those distant lesions being = 54 weeks.=20 Histologically confirmed radiation necrosis alone was observed in nine = cases and=20 in two others in combination with tumor recurrence. They estimated the = actuarial=20 1 year incidence of radiation necrosis without tumor at 23%. The = authors=20 made an attempt to assess functional status noting baseline median = Mini-Mental=20 Status Exam scores were 28.5. This remained stable at 29 at = 6 months and=20 12 months amongst the patients still surviving at those intervals.=20 Additionally the median FACT-BR score at baseline was 130 and at = 12 months=20 it was 112. Median survival was 40 weeks at the 1 year = follow-up point=20 of the report and only four of the 35 deaths that had occurred were due = to tumor=20 progression within the central nervous system and all were at sites not = treated=20 with the Gliasite. This data was obtained prospectively, but without = meaningful=20 concurrent comparative data rendering it class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>].=20 </P> <P class=3D"">Sills et al. provided a preliminary report captured in a = conference=20 proceeding search of a series of patients with one to three brain = metastases.=20 One lesion was treated with =93balloon brachytherapy=94 (presumably the = Gliasite=20 Radiation Therapy System) to a dose of 60 Gy at 5 mm and the = other=20 lesions treated with stereotactic radiosurgery. Of the 48 cases reported = (of a=20 planned enrollment of 50) one case had local recurrence at 3 months = and=20 another at 9 months. Radiation necrosis was confirmed surgically in = one=20 case 12 months after treatment and suspected by positron emission=20 tomography in another after 15 months. The primary outcome measures = planned=20 were 6 month and 1 year local control and this was not = reported. This=20 data was obtained prospectively, but is clearly incomplete and without=20 meaningful concurrent comparative data rendering it as class III = evidence=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR27">27</A></CITE>].=20 </P> <P class=3D"">In another preliminary report captured in a conference = proceeding=20 search, a study assessing radiation necrosis in brain metastases = patients by=20 Burri et al. provided a retrospective look in their practice database of = 20=20 cases that underwent resection followed by Gliasite implantation as = initial=20 primary therapy without WBRT. The chosen dose was 60 Gy though the = depth of=20 the dose is specified in only seven of the cases. Seven cases required = surgical=20 debridement of symptomatic progressive imaging changes that proved to be = radiation necrosis for a crude reoperation rate of 35%. They attempted = to=20 estimate an actuarial risk of reoperation in those with radiation = necrosis=20 noting it as 7% at 6 months reaching 84% at 24 months with a = median=20 time to that operation of 17 months. The authors conclude that = radiation=20 necrosis is a substantial risk with the use of the Gliasite device for = the dose=20 regimens they used for metastatic disease. The retrospective nature of = this=20 series is unable to filter for bias in case selection or nonsurgical = management=20 and provides no comparison to other modalities of radiation to determine = if=20 their findings are truly out of the ordinary for their practice. Thus = this case=20 series with limited clinical background and no comparative component = meets the=20 criteria to provide class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR28">28</A></CITE>].=20 The frequency of radiation necrosis with the use of Gliasite was = substantial in=20 the Rogers et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>]=20 and the Burri et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR28">28</A></CITE>]=20 studies. Additionally, the minimally described assessments for radiation = necrosis in the Sills et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR27">27</A></CITE>]=20 study results in the level 3 recommendation that this technique is best = utilized=20 in the clinical trial setting for metastatic brain tumors. </P></DIV> <DIV class=3D""><A name=3DSec19></A> <H4 class=3DSection3>Case series</H4> <P class=3D"">Bogart et al., report a series of 15 cases of solitary = metastases=20 from NSCLC treated with surgical resection and permanent <SUP>125</SUP>I = seeds=20 implanted on the surface of the tumor bed. Median KPS was 70 and ten of = the 15=20 individuals had the intracranial disease as the only active site. The = planned=20 dose was 5 cGy/h with estimated cumulative doses of = 80=96160 cGy to the=20 tumor bed [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR29">29</A></CITE>].=20 Median follow-up and survival was 14 months. The median time to = recurrence=20 was 9 months. Recurrences within the brain were local in 2 l, = distant=20 in two and both in one. One individual succumbed to an overwhelming = fungal=20 infection. None developed symptomatic radionecrosis. The authors = conclude that=20 this modality may be useful for selected patients but that further = studies in a=20 larger number of patients were warranted [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>].=20 </P> <P class=3D"">When looking at a series of 26 patients with single brain = metastasis=20 with very high performance status (median KPS 90) Dagnew et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>],=20 found a median actuarial survival of 17.8 months after surgical = resection=20 and placement of permanent low activity <SUP>125</SUP>I seeds with an = estimated=20 dose of 150 Gy to the tumor bed resection perimeter taking into = account=20 tumor cavity collapse. All cases reportedly had controlled systemic = disease from=20 a variety of primary sites. Only one patient had local recurrence and = only two=20 died of neurologic disease. Thirty-eight percent developed tumors = elsewhere in=20 the brain that on their review was higher than in patients who received = WBRT as=20 an initial part of their treatment (as previously seen in studies by = Noordijk et=20 al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR30">30</A></CITE>]=20 and Patchell et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR31">31</A></CITE>]).=20 One individual had deep venous thrombosis and pulmonary embolus = perioperatively.=20 Symptomatic radiation necrosis occurred in two individuals requiring = surgical=20 debridement. Both of those patients had tumors that had exceeded = 3 cm in=20 greatest diameter (3.1 and 5 cm). This case series with no = comparative=20 component meets the criteria to provide class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>].=20 </P> <P class=3D"">In 1997 Schulder et al., reported their experience with 13 = cases of=20 brain metastases treated with surgical resection and implantation of = permanent=20 low activity <SUP>125</SUP>I seeds. Included were individuals with = recurrent=20 tumors having already failed WBRT (8 patients), or who had initially = refused=20 WBRT with metastases too large for stereotactic radiosurgery (5 = patients). The=20 median calculated dose of <SUP>125</SUP>I was 82 Gy. This was a = good=20 performance status group of patients with a mean KPS of 84 and absent or = stable=20 systemic disease. Two patients died early; one who required evacuation = of a=20 hematoma in the resection cavity on the day after implantation then died = of=20 pulmonary embolus 2 weeks later and one with postoperative adult=20 respiratory distress syndrome. The mean survival of the remaining 11 was = 9 months and all had local control. One individual required surgery = for=20 symptomatic radiation necrosis and another for a combination of tumor = and=20 radiation necrosis. One patient developed a symptomatic cerebrospinal = fluid leak=20 requiring repair. This case series with no relative comparison to = another=20 therapy meets the criteria to provide class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>].=20 The high early mortality rate in this small study suggests that the use = of low=20 activity <SUP>125</SUP>I seeds in brain metastases should be relegated = to=20 properly conducted clinical trials. </P></DIV></DIV> <DIV class=3D""><A name=3DSec20></A> <DIV class=3DHeading3>Surgery and local chemotherapy with or without = whole brain=20 radiation therapy</DIV> <P class=3D"">Two single arm studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>]=20 met the criteria for inclusion of their data in this portion of the = guideline.=20 </P> <P class=3D"">In an assessment of an alternative modality to local = radiation=20 therapy, Ewend et al., described their experience with a prospectively = evaluated=20 group of 25 cases of newly diagnosed solitary metastatic tumors in good=20 performance status patients treated with surgical resection and Gliadel = wafer=20 implantation followed by WBRT (44 Gy in 22 fractions). The primary = goal was=20 to assess toxicity of this combination therapy, and the serious = toxicities=20 reported included seizures (<I>n</I> =3D 1), seizures and = respiratory=20 failure (<I>n</I> =3D 1), and the moderate toxicities included = nausea=20 (<I>n</I> =3D 2), constipation (<I>n</I> =3D 3), = right eye pain=20 (<I>n</I> =3D 1) and fever (<I>n</I> =3D 1). Median = follow-up=20 was 36.1 weeks and at that point median survival was 33 weeks. = No=20 local recurrences were reported but four patients developed distant = intracranial=20 recurrences and two patients had new metastases in the spinal canal. Of = the 16=20 deaths observed five were neurologic in nature. This data was obtained=20 prospectively, but without meaningful concurrent comparative data = rendering=20 class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P class=3D"">In a study of the feasibility of intracavitary=20 5-fluoro-2′-deoxyuridine (FdUrd) Nakagawa et al., report on six = brain metastases=20 patients in a series of 13 cases with malignant brain tumors. They point = out=20 that the goal of the use of this agent is to inhibit tumor DNA synthesis = by its=20 metabolite 5-fluoro-2=92deoxy-5=92-monophosphate. After claiming to show = intrathecal=20 administration of FdUrd was safe, the authors placed an Ommaya reservoir = in=20 =93small=94 fresh resection cavities and then administered 25=9630 daily = injections of=20 1=965 micrograms. They report no adverse events and three complete = responses (of=20 3, 10 and 32 weeks, respectively), one with stable disease and two = with=20 progressive disease. However, median follow-up time is not reported. = This data=20 was obtained prospectively, but with less than usual detail on = pretreatment and=20 post-treatment data and is without meaningful concurrent comparative = data=20 rendering it as class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec21></A> <DIV class=3DHeading3>Interstitial radiosurgery</DIV> <P class=3D"">Two case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>]=20 met the criteria for inclusion of their data in this portion of the = guideline.=20 To assess a device termed the Photon Radiosurgery System (PRS), Curry et = al.,=20 describe its use in the treatment of 60 patients with metastatic brain = tumors;=20 37 with solitary lesions and 23 with multiple lesions. They describe the = device=20 as a light weight x-ray generator that produces a point source of = low-energy=20 photons. The median age of the subjects was 58 years (range of=20 18=9683 years) and median KPS was 90. Prior treatment was variable. = PRS was=20 applied in cases not deemed suitable for resection due to location or = which were=20 undergoing diagnostic biopsy. Seven lesions were larger than 3 cm = in=20 diameter and only one in the entire series was in the cerebellum. The = device was=20 introduced utilizing a stereotactic frame. The median dose was = 16 Gy to a=20 point 2 mm beyond the enhancing tumor margin. The authors chose to = report=20 local control as their primary outcome and did so after a median = follow-up of=20 6 months (with a range of 5 days to 31 months). = Seventy-two=20 lesions were treated. Local control was present in 81%. Median survival = was=20 8 months from treatment. Of the 46 cases that went onto death, 30% = were=20 neurologic in nature. Four patients experienced perioperative seizures = that were=20 easily controlled with anticonvulsant medications and were not = recurrent, three=20 experienced transient neurological deficits thought to be associated = with the=20 biopsy or due to treatment induced cerebral edema, and two experienced = biopsy=20 related hemorrhages. Three patients experienced symptomatic radiation = necrosis=20 requiring surgical debridement and corticosteroid therapy. This case = series with=20 no concurrent comparison to another therapy meets the criteria to = provide class=20 III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>].=20 </P> <P class=3D"">In an attempt to avoid WBRT as an initial treatment in = patients with=20 metastatic brain tumors Nakamura et al., reported a case series of 43 = patients=20 whose solitary lesions were treated with intraoperative radiosurgery = with=20 high-energy electron beams generated by a 20 MeV betatron. Therapy = was=20 delivered over 5=9610 min to a dose of 18=9625 Gy with = 8=9616 MeV to=20 one cm beyond the margins of a fresh resection bed. They also mention = that=20 progression was treated with additional radiation but this was not = standardized.=20 One year survival was 53%. Median follow-up was not reported, but seven = patients=20 developed local recurrence and seven patients developed brain = recurrences=20 distant from the primary site. Two individuals developed radiation = necrosis at=20 the treatment site but were managed without surgery. The authors discuss = other=20 patients treated for brain metastases at their institution utilizing = various=20 combinations of therapy but fail to provide systematic pretreatment and=20 follow-up data so as to make a meaningful comparison. Thus the data from = this=20 paper qualifies as class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>].=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec22></A> <HR> <DIV class=3Dheading2>Interstitial therapy summary</DIV> <P class=3D"">Interstitial therapies are appealing as their intent is to = maximize=20 treatment of the metastatic pathology and preserve surrounding normal = tissue.=20 The data presented here does not allow creation of level 1 or level 2=20 recommendations. The interstitial use of radiation and cytotoxic = chemotherapy=20 appears feasible but not without toxicity. Furtherance of these = modalities will=20 be dependent on truly prospective and comparative study designs in order = to=20 obtain meaningful information. </P> <DIV class=3D""><A name=3DSec23></A> <DIV class=3DHeading3>New chemotherapeutic agents</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided 31 unique studies that = met the=20 criteria for support of guidelines recommendations regarding the use of=20 chemotherapeutic agents in the management of brain metastases = (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab4">4</A>).=20 The use of temozolomide was reported in 25 studies of which two were = evidence=20 class I studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>],=20 two were evidence class II studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>],=20 and 21 were evidence class III studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>].=20 In most of the studies included in this discussion the primary tumor = treated was=20 melanoma, though other primary tumor sites were addressed.<A = name=3DTab4></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 4 </SPAN>Summary = of primary=20 chemotherapy 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/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"">Tumor response</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"">TMZ</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Abrey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">6.62 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete response 0/41 (0%)</P> <P class=3D"">Partial response 2/41 (4.9%)</P> <P class=3D"">Stable disease 15/41 (36.6%)</P> <P class=3D"">Progressive disease 17/41 (41.5%)</P> <P class=3D"">Not assessed 7/41 (17.1%)</P></TD> <TD align=3Dleft> <P class=3D"">Overall in brain: 1.97 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Addeo [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + TMZ (<I>n</I> =3D 59) = </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">13 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 44% (CR: 5/59; PR 21/59)</P> <P class=3D"">Stable Disease: 19/59 (32.3%)</P> <P class=3D"">Progressive Disease: 14/59 (23.7%)</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression: = 9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Agarwala [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 151) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">3.2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 6% (CR 1/151; PR 8/151)</P> <P class=3D"">Stable disease: 40/151 (26%)</P> <P class=3D"">Progressive disease: 73/151 (48%)</P> <P class=3D"">Not evaluable: 29/151 (19%)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: Pts with prior = chemo:=20 1 month</P> <P class=3D"">Chemo na=EFve pts: 1.2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Antonadou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">Randomized phase II trial</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 23) </P> <P class=3D"">G2: WBRT + TMZ (<I>n</I> =3D 25) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from lung, breast or unknown primary</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7.0 months</P> <P class=3D"">G2: 8.6 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (Of evaluable pts)</P> <P class=3D"">G1: OR 67% (CR 7/21, PR 7/21)</P> <P class=3D"">G2: OR 96% (CR 9/24, PR 14/24) = (<I>p</I> =3D 0.017)=20 </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bafaloukos [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR39">39</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Sub-group analysis of two Phase II studies</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ-based chemotherapy (<I>n</I> =3D 25) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">4.7 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 24% (CR 0/25;</P> <P class=3D"">PR 6/25)</P> <P class=3D"">Stable disease 5/25</P> <P class=3D"">Progressive disease 13/25</P> <P class=3D"">Not evaluable 1/25</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression:</P> <P class=3D"">2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Boogerd [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Sub-group analysis of three prospective studies</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ =B1 immunotherapy = (<I>n</I> =3D 52 with=20 BM) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">5.6 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Only reported for sub-group of 13/52 pts who had a = response to=20 TMZ at extra-cranial sites:</P> <P class=3D"">Complete response 3/13</P> <P class=3D"">Partial response 2/13</P> <P class=3D"">Stable disease 6/13</P></TD> <TD align=3Dleft> <P class=3D"">NR overall</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Caraglia [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + pegylated liposomal doxorubicin=20 (<I>n</I> =3D 19) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">10 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR36.8% (CR 3/19; PR 4/19)</P> <P class=3D"">Stable Disease 8/19 (42.1%)</P> <P class=3D"">Progressive Disease 4/19 (21%)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 5.5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + cisplatin = (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">5.5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response both in brain +</P> <P class=3D"">Extra-cranial sites:</P> <P class=3D"">Complete response 1/32</P> <P class=3D"">Partial response 8/32</P> <P class=3D"">Partial response in brain only 1/32</P> <P class=3D"">Stable disease 5/32</P> <P class=3D"">Progressive disease 6/32</P> <P class=3D"">Not evaluable 11/32</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression for all pts:=20 2.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 28) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">4.5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 4% (CR 0/27; PR 1/27)</P> <P class=3D"">Stable disease 4/27</P> <P class=3D"">Progressive disease or death: 14/27</P> <P class=3D"">Not assessable: 3/27</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression: = 3 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Conill [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>]=20 (2006) </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 Gy/5 fractions + TMZ based = chemotherapy=20 (<I>n</I> =3D 11) </P> <P class=3D"">G2: 30 Gy/10 fractions + TMZ based = chemotherapy=20 (<I>n</I> =3D 10) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.0 months G2: 4.0 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Data not reported by group;</P> <P class=3D"">No statistically significant difference between = groups=20 (<I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Cortot [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + cisplatin followed by WBRT=20 (<I>n</I> =3D 50; 68% had WBRT) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response (CR 2%<B>;</B> PR 10%) </P> <P class=3D"">Stable disease: 42%</P> <P class=3D"">Progressive disease: 40%</P> <P class=3D"">Not assessable: 6%</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression: = 2.3 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Giorgio [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 30) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">6 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete response 2/30 (6.7%)</P> <P class=3D"">Partial response 1/30 (3.3%)</P> <P class=3D"">Stable disease 3/30 (10%)</P> <P class=3D"">Progressive disease 24/30 (80%)</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression of brain metastases in = all pts:=20 3.6 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hofmann [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR45">45</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ =B1 SRS or WBRT = (<I>n</I> =3D 35) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">8 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain + extra-cranial = sites:</P> <P class=3D"">(Of 34 evaluable pts)</P> <P class=3D"">Complete remission: 1/34 (3%)</P> <P class=3D"">Partial remission: 2/34 (6%)</P> <P class=3D"">Stable disease: 9/34 (26.4%)</P> <P class=3D"">Mixed response (PR or stable disease in brain, but=20 extra-cranial disease progression): 5/34 (14.7%)</P> <P class=3D"">Progressive disease: 17/34 (50%)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: = 5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hwu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + thalidomide = (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete response 2/26</P> <P class=3D"">Partial response 1/26</P> <P class=3D"">Minor response/stable: 7/26</P> <P class=3D"">Progressive disease: 4/26</P> <P class=3D"">Unknown 1/26</P> <P class=3D"">Not assessable 11/26</P></TD> <TD align=3Dleft> <P class=3D"">Median duration of response or stable disease in = brain:=20 4 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Iwamoto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>]=20 (2008) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 38) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/refractory BM</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 5% (CR 1/38; minor response = 1/38)</P> <P class=3D"">Stable disease 5/38</P> <P class=3D"">Progressive disease 29/38</P> <P class=3D"">Not evaluable 2/38</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: = 1.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Janinis [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR48">48</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 11) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 8 pts evaluable)</P> <P class=3D"">Partial response 1/8</P> <P class=3D"">Minor response 3/8</P> <P class=3D"">Stable disease 1/8</P> <P class=3D"">Progressive disease: 3/8</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Kouvaris [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + TMZ (<I>n</I> =3D 33) = </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">12 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">After 3 cycles of TMZ:</P> <P class=3D"">OR 54.5% (CR 7/33;</P> <P class=3D"">PR 11/33)</P> <P class=3D"">After 6 cycles of TMZ:</P> <P class=3D"">OR 57.6% (CR 8/33; PR 11/33)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 11 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Krown [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + thalidomide = (<I>n</I> =3D 16) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">23.9 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 0/16 (ITT analysis)</P></TD> <TD align=3Dleft> <P class=3D"">Progression-free survival: = 7.3 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Larkin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I/II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + lomustine = (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (In phase II; = <I>n</I> =3D 20) </P> <P class=3D"">Response rate 0/20</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Margolin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + WBRT (<I>n</I> =3D 31) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">6 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 9.7% (CR 1/31; PR 2/31)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Omuro [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 21) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">17 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 18 evaluable pts)</P> <P class=3D"">Partial response 1/18</P> <P class=3D"">Minor response 1/18</P> <P class=3D"">Stable disease 6/18</P> <P class=3D"">Progressive disease 10/18</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Panagiotou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>]=20 (2005) </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 5) </P> <P class=3D"">G2: TMZ (initial tx) + WBRT (after = progression)=20 (<I>n</I> =3D 17) </P> <P class=3D"">G3: WBRT (<I>n</I> =3D 28) </P> <P class=3D"">G4: Supportive care (<I>n</I> =3D 14) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 12 months</P> <P class=3D"">G2: 5 months</P> <P class=3D"">G3: 3 months</P> <P class=3D"">G4: 2 months</P> <P class=3D"">(Survival curves G2 vs. G3 log-rank;=20 <I>p</I> =3D 0.0267) </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""> Rivera [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + capecitabine = (<I>n</I> =3D 24) </P></TD> <TD align=3Dleft> <P class=3D"">BM from breast cancer</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 22 evaluable pts)</P> <P class=3D"">OR 18% (CR1/22; PR 3/22)</P> <P class=3D"">Minor response or stable disease 11/22</P> <P class=3D"">Progressive disease 7/22</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression of brain metastases:=20 12 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schadendorf [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 45) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">4.1 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 4.4% (CR 0/45; PR 2/45)</P> <P class=3D"">Stable disease 5/45</P> <P class=3D"">Progressive disease 33/45</P> <P class=3D"">Not evaluable 5/45</P></TD> <TD align=3Dleft> <P class=3D"">NR overall</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Verger [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft> <P class=3D"">Randomized phase II trial</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 41) </P> <P class=3D"">G2: WBRT + TMZ (<I>n</I> =3D 41) = </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 3.1 months</P> <P class=3D"">G2: 4.5 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response in brain at 30 days: (by ITT)</P> <P class=3D"">G1: OR 32% (CR 2/41, PR 11/41)</P> <P class=3D"">G2: OR 32% (CR 2/41, PR 11/41) = (<I>p</I> =3D NS) </P> <P class=3D"">Response in brain at 90 days:</P> <P class=3D"">G1: OR 2/41 (CR 0/41, PR 2/41)</P> <P class=3D"">G2: OR 7/41 (CR 1/41, PR 6/41) = (<I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median: Not reported</P> <P class=3D"">% BM progression-free at 90 days:</P> <P class=3D"">G1: 54%</P> <P class=3D"">G2: 72% (<I>p</I> =3D 0.03) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Fotemustine</P></TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Br=F6cker [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + fotemustine = (<I>n</I> =3D 13) </P></TD> <TD align=3Dleft> <P class=3D"">Progressive multiple BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">Overall: Not reported</P> <P class=3D"">Pts with partial response/stable disease: = 6 months</P> <P class=3D"">Other pts: 2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (12 evaluable pts)</P> <P class=3D"">Complete response: 0/13</P> <P class=3D"">Partial response 4/13</P> <P class=3D"">Stable disease 3/13</P> <P class=3D"">Progressive disease 6/13</P> <P class=3D"">Not assessable: 1/13</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Chang [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Dacarbazine + fotemustine = (<I>n</I> =3D 34)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">4.5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 12% (CR 2/34; PR 2/34)</P> <P class=3D"">Stable disease 9/34</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Cotto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR62">62</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Fotemustine + Cisplatin = (<I>n</I> =3D 31)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">16 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 25 evaluable pts)</P> <P class=3D"">OR 16% (CR 2/25; PR 2/25)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Jacquilat [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Fotemustine (<I>n</I> =3D 39) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">26 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 28% (CR 2/39; PR 9/39)</P> <P class=3D"">Stable disease 9/39</P> <P class=3D"">Progressive disease 19/39</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mornex [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>]=20 (2003) </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: Fotemustine (<I>n</I> =3D 39) </P> <P class=3D"">G2: Fotemustine + WBRT = (<I>n</I> =3D 37)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 86 days</P> <P class=3D"">G2: 105 days</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain at day 50 (by ITT)</P> <P class=3D"">G1: OR 5.1% (CR 0/39, PR 2/39)</P> <P class=3D"">G2: OR 8.1% (CR 0/37, PR 3/37) = (<I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression in brain:</P> <P class=3D"">G1: 49 days</P> <P class=3D"">G2: 80 days</P> <P class=3D"">(BM progression-free curves; Wilcoxon:=20 <I>p</I> =3D 0.03; log-rank: = <I>p</I> =3D 0.069)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ulrich [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P = class=3D"">WBRT + fotemustine =B1 dacarbazine=20 (<I>n</I> =3D 12) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">Mean survival of responders:</P> <P class=3D"">8.2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete remission 4/12</P> <P class=3D"">Partial remission 2/12</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">Mean progression free survival:=20 6.1 months</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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>LR</I> Local recurrence at original site in = brain,=20 <I>MGd</I> Motexafin-gadolinium, <I>NR</I> Not reported, <I>NS</I> Not=20 significant, <I>NSCLC</I> Non-small cell lung cancer, <I>OR</I> = Objective=20 response, <I>PR</I> Partial response, <I>Pts</I> Patients, <I>RCT</I> = Randomized=20 control trial, <I>SRS</I> Stereotactic radiosurgery, <I>TMZ</I> = Temozolomide,=20 <I>WBRT</I> Whole-brain radiation therapy=20 </DIV></DIV></DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec24></A> <HR> <DIV class=3Dheading2>Temozolomide</DIV> <DIV class=3D""><A name=3DSec25></A> <DIV class=3DHeading3>Prospective randomized phase II studies</DIV> <P class=3D"">In the first of the class I studies Antonadou et al., = carried out a=20 randomized phase II study of 48 individuals with lung cancer, breast = cancer or=20 unknown primaries. Group 1 received WBRT to 40 Gy in 2 Gy = fractions=20 and group 2 received oral temozolomide (TMZ, 75 mg/m=B2/d) = concurrent with=20 WBRT 40 Gy in 2 Gy fractions and then continued TMZ therapy=20 (200 mg/m=B2/d) for 5 days every 28 days for an = additional maximum=20 of 6 cycles after WBRT was completed. The clinical and pathologic=20 characteristics of the groups were well balanced. The response rate in = group 2=20 was 96% as opposed to 67% in group 1, a significant difference=20 (<I>p</I> =3D 0.017). This better response rate was at the = cost of=20 significantly more nausea and vomiting in group 2. There was no grade 3 = or grade=20 4 myelosuppression. However, median survival was 7.0 months in = group 1 and=20 8.6 months in group 2, a difference that did not reach significance = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>].=20 </P> <P class=3D"">The second class I study by Verger et al., was also a = randomized=20 phase II study of patients with newly diagnosed brain metastases from = any=20 source. Group 1 received 30 Gy WBRT in 10 fractions and group 2 = received=20 30 Gy WBRT in 10 fractions with concurrent TMZ during radiation=20 (75 mg/m=B2/day), followed by two cycles of TMZ = (200 mg/m=B2/day) for=20 5 days of a 28 day cycle. The clinical and pathology = characteristics=20 of each group were not significantly different. Progression free = survival from=20 brain metastases 90 days after randomization was 72% in group 2 and = 54% in=20 group 1, a statistically significant advantage = (<I>p</I> =3D 0.03). Also=20 group 1 had a greater percentage dying a neurologic death (69%) than in = group 2=20 (41%), again a significant difference (<I>p</I> =3D 0.029). = Despite=20 these differences, there was no advantage in median survival of group 2 = over=20 group 1 (4.5 months and 3.1 months, respectively) and no = difference in=20 response rates. Additionally, clinically significant toxicity was only = observed=20 in group 2 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>].=20 In summary, neither of these well done randomized phase II studies = demonstrated=20 a meaningful benefit to survival by adding TMZ. </P></DIV> <DIV class=3D""><A name=3DSec26></A> <DIV class=3DHeading3>Retrospective cohort analyses</DIV> <P class=3D"">Both of the class II studies regarding the use of TMZ were = retrospective cohort analyses [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>].=20 In the first study Panagioutou et al., described their experience with = 64=20 patients with melanoma brain metastases. Four groups were evaluated = according to=20 treatment. Group A was treated with surgery followed by WBRT, Group B = was=20 treated with TMZ at initial diagnosis and with WBRT at progression, = Group C was=20 treated with WBRT alone, and Group D received supportive care alone. The = median=20 survivals were 12, 5, 3, and 2 months, respectively. The survival = in the=20 TMZ at initial diagnosis and WBRT at progression group was significantly = greater=20 than the WBRT alone group (<I>p</I> =3D 0.0267 by log rank). = Patient=20 characteristics influenced treatment selection. Age and intracranial = extent of=20 disease were not well balanced and performance status was not assessed = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>].=20 In a study that mainly looked at differing radiation doses Conill et = al.,=20 reviewed a group of 21 individuals with melanoma brain metastases who = were=20 treated with WBRT (20 Gy in 5 fractions) and TMZ-based chemotherapy = (<I>n</I> =3D 11), or WBRT (30 Gy in 10 fractions) and = TMZ-based=20 chemotherapy (<I>n</I> =3D 11). The actual chemotherapy = regimens varied=20 substantially, with some patients receiving other agents in addition. = The extent=20 of disease and performance status was reasonably well balanced between = the two=20 groups and the median survival in both groups was 4 months = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>].=20 Again, in these class II studies, one cannot conclude TMZ imparts a = survival=20 advantage. </P></DIV> <DIV class=3D""><A name=3DSec27></A> <DIV class=3DHeading3>Prospective phase II studies</DIV> <P class=3D"">Among the 21 remaining studies qualifying for inclusion in = this=20 guideline all were class III data. Five were prospective phase II = studies in=20 which TMZ was utilized alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>].=20 Agarwala et al., reported their prospective experience with 151 patients = with=20 newly diagnosed brain melanoma metastases treated with TMZ=20 (150 mg/m<SUP>2</SUP>/day for patients with prior chemotherapy, or=20 200 mg/m<SUP>2</SUP>/day for chemotherapy na=EFve patients, for = 5 days,=20 every 28 days for 1 year or until disease progression or = unacceptable=20 toxicity). Median survival was 3.2 months and objective response = (complete=20 response or partial response) was noted in 6% [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>].=20 Schadendorf et al., treated 45 individuals with known melanoma who had = developed=20 new brain metastases with TMZ (125 mg/m<SUP>2</SUP>/day in patients = who had=20 received prior chemotherapy or 150 mg/m=B2/day in previously = untreated=20 patients, on days 1=967 and days 15=9621 very 28 days). Median = survival was=20 4.1 months with two partial responses and five patients with stable = disease=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>].=20 In another study of newly diagnosed brain metastases Christadoulou et = al. looked=20 at individuals with a wide variety of primaries that had already = received=20 substantial systemic therapy for their cancer. All = (<I>n</I> =3D 28)=20 received TMZ (150 mg/m<SUP>2</SUP>/day for 5 days every = 4 weeks=20 until progression or unacceptable toxicity). Median survival in the = entire group=20 was 4.5 months with only one partial response [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>].=20 Abrey et al., looked at 41 individuals with recurrent or progressive = brain=20 metastases from various primaries (22 were NSCLC) treated with TMZ = (patients who=20 had received chemotherapy before received TMZ = 150 mg/m<SUP>2</SUP>/day for=20 5 days, and chemotherapy na=EFve patients received=20 200 mg/m<SUP>2</SUP>/day for 5 days with treatment cycles = repeated=20 every 28 days). Two partial responses were observed. Overall median = survival was 6.62 months in all participants [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>].=20 Giorgio et al., looked at a series of patients with NSCLC whose brain = metastases=20 had progressed after WBRT and one regimen of chemotherapy=20 (<I>n</I> =3D 30). Two complete responses and one partial = response were=20 reported. Median survival was six months [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>].=20 Though individuals with NSCLC seemed to survive slightly longer than = those with=20 melanoma in these five studies no meaningful comparison or statistical=20 assessment can support such a conclusion. </P> <P class=3D"">In a sixth prospective single armed study Janinis reported = on 11=20 patients with melanoma brain metastases who had not received = radiotherapy, who=20 were treated with TMZ (200 mg/m<SUP>2</SUP>/day for 5 days = every=20 28 days for chemotherapy na=EFve patients and = 150 mg/m<SUP>2</SUP>/day=20 for 5 days every 28 days for patients treated with prior=20 chemotherapy). Survivals ranged from 10 days to over 13 months = but no=20 median was reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR48">48</A></CITE>].=20 Though this publication met the criteria for being included in this = guideline,=20 the small size and lack of comparative data does not yield information = that=20 provides direction for therapy in brain metastases. </P> <P class=3D"">In three of the prospective phase II studies yielding = class III=20 data, TMZ was used with WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>].=20 Margolin et al., assessed 31 individuals with newly diagnosed melanoma = brain=20 metastases treated with TMZ at 75 mg/m<SUP>2</SUP>/day started on = day 1 and=20 continued daily for 6 weeks and then repeated every 10 weeks = along=20 WBRT to a total dose of 30 Gy in 10 fractions on days 1=965 and = 8=9612. Though=20 all cases had a WHO performance status of 0 or 1 the median survival was = just=20 6 months and only one complete response and two partial responses = were=20 observed [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>].=20 In a more recent study Addeo et al., describe the use of WBRT to a dose = of=20 30 Gy in 10 fractions with concomitant TMZ = (75 mg/m<SUP>2</SUP>/day)=20 for 10 days, and subsequent TMZ (150 mg/m<SUP>2</SUP>/day = every=20 28 days) for up to 6 cycles in 59 patients with newly diagnosed = brain=20 metastases from various sources. Median survival was 13 months with = 5=20 complete responses and 21 partial responses being noted to yield a 44% = objective=20 response rate. In another study looking at brain metastases from a = variety of=20 primary sites, Kouvaris et al., reported the use of combined therapy = with WBRT=20 to a total dose of 36 Gy in 12 fractions given in 16 days = along with=20 TMZ 60 mg/m=B2/day (days 1=9616) followed by 6 cycles of TMZ=20 (200 mg/m=B2/day for 5 consecutive days every 28 days). Median = survival=20 was 12 months with seven complete responses and 11 partial = responses being=20 noted for an overall objective response rate of 54.5% with the objective = response rate in patients with lung cancer being 78.6%. Interestingly, = 45.5% of=20 individuals in this study experienced hepatotoxicity, attributed to the = use of=20 anticonvulsants in these patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>].=20 The improved survival seen here and in the Addeo et al., study as = opposed to the=20 Margolin study may be more related to the underlying primary tumor = histologies=20 than to the advantage provided by the alteration in the TMZ = administration=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>].=20 </P> <P class=3D"">One other prospective phase II study of WBRT and TMZ also = included=20 the use of cisplatin but with both cytotoxic agents administered before=20 radiation [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>].=20 Cortot et al., studied 50 patients with NSCLC brain metastases treated = with TMZ=20 (200 mg/m<SUP>2</SUP>/day for 5 days every 28 days) and = cisplatin=20 (75 mg/m<SUP>2</SUP>) on day 1 of each cycle, for up to 6 cycles = followed=20 by WBRT to a total of 30 Gy in 10 fractions. WBRT was performed at = time of=20 progressive disease (at any time) or in patients with stable disease = after 4=20 cycles. Median survival was 5 months and one complete response and = five=20 partial responses were noted [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>].=20 Though methodological differences prevent meaningful comparisons between = this=20 and the studies of Addeo, Kouvaris and Margolin, the addition of = cisplatin did=20 not appear to provide an overt survival or response benefit. </P> <P class=3D"">In the six remaining prospective phase II studies TMZ was = used in=20 combination with a variety of other systemic agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>].=20 These included thalidomide, cisplatin, vinorelbine, pegylated liposomal=20 doxorubicin, and lomustine utilized for a variety of tumor types and at = either=20 new diagnosis or at recurrence. Median survival was as short as = 2 months in=20 the report by Larkin et al., who utilized TMZ at = 150 mg/m<SUP>2</SUP> on=20 days 1 through 5 every 28 days and lomustine = 60 mg/m<SUP>2</SUP> on=20 cycle day 5 every 56 days in patients with newly diagnosed melanoma = brain=20 metastases[<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>].=20 The longest median survival in this group of six studies was = 10 months in=20 the report of Caraglia et al., who used TMZ at 200 mg/m=B2 on days = 1 through=20 5 and pegylated liposomal doxorubicin at 35 mg/m=B2 on day 1 of = every=20 28 day cycle for up to 8 cycles in individuals with progressive = metastases=20 failing initial therapy. In this study, only one individual had a = melanoma=20 primary[<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>].=20 Here again, the underlying characteristics of the different studies are = too=20 disparate to allow meaningful comparisons to establish the superiority = or=20 inferiority of one regimen to another. They do, however, reflect the = known poor=20 prognosis of patients with melanoma once intracranial metastases develop = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec28></A> <DIV class=3DHeading3>Prospective phase I studies</DIV> <P class=3D"">There were two prospective phase I studies utilizing TMZ = and other=20 management in the series of papers meeting this guideline=92s criteria = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>].=20 In the first Omuro et al., describe the use of 28 day cycles of TMZ = at=20 150 mg/m<SUP>2</SUP> on days 1 through 7 and 15 through 21 and = vinorelbine=20 on days 1 and 8 using escalating doses with a starting dose of=20 15 mg/m<SUP>2</SUP> with increments of 5 mg/m<SUP>2</SUP> for = each=20 cohort of 3=966 patients until 30 mg/m<SUP>2</SUP>. The maximum = tolerated=20 dose was declared at 30 mg/m<SUP>2</SUP> and, though not a primary = goal of=20 the study, it was noted median survival of the patients treated was=20 17 weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>].=20 In the other study Rivera et al., looked for a maximum tolerated dose of = TMZ and=20 capecitabine. Four sequential cohorts were treated at different dosing = levels on=20 days 1 through 5 and days 8 through 12 with cycles repeated every = 21 days.=20 Respective dosing ranges of capecitabine and TMZ were=20 1600=962000 mg/m<SUP>2</SUP> and 50=96150 mg/m<SUP>2</SUP>. = Maximum=20 tolerated dose was not reached. No median survival was reported but, = among the=20 24 cases enrolled one complete response and two partial responses were = noted=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>].=20 Though these two studies meet criteria for inclusion in these = guidelines, they=20 add little to development of a consensus on how TMZ, alone or in = combination=20 with other agents would play a role in the therapy of brain metastases.=20 </P></DIV> <DIV class=3D""><A name=3DSec29></A> <DIV class=3DHeading3>Combined subgroup analyses from multiple = publications</DIV> <P class=3D"">Two of the studies involving TMZ therapy of brain = metastases were=20 subgroup analyses combined from prior prospective studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR39">39</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>].=20 Bafaloukos et al., combined the data from two publications of the = Hellenic=20 Cooperative Oncology Group evaluating patients with melanoma brain = metastases.=20 Twenty-five individuals treated with TMZ at a dose of=20 150=96200 mg/m<SUP>2</SUP>/day on days 1 through 5 every = 4 weeks alone=20 or with either docetaxel (80 mg/m<SUP>2</SUP> on day 1) or = cisplatin=20 (75 mg/m<SUP>2</SUP> on day 1). Median survival combining all = patients was=20 4.7 months. Six partial responses were observed distributed between = the=20 three groups. No obvious superiority of one regimen was discerned over = another=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR39">39</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR57">57</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR58">58</A></CITE>].=20 In the publication by Boogerd et al., data was combined from three = different=20 studies. Fifty-two patients with brain metastases were evaluable who = were=20 treated with TMZ at doses from 150 to 250 mg/m<SUP>2</SUP>/day for=20 5 days every 4 weeks followed by immunotherapy=20 granulocyte=96macrophage-colony stimulating factor (2.5 μg/kg), = interleukin-2 (4=20 MIU/m<SUP>2</SUP>), and IFNα (5 MIU fixed dose) for 12 days=20 (<I>n</I> =3D 23) or who were treated with TMZ alone=20 (200 mg/m<SUP>2</SUP>/day for 5 days every 4 weeks)=20 (<I>n</I> =3D 29). Out of the 52 patients the authors focused = on the 13=20 with evidence of systemic response noting that their neurologic = stabilization or=20 responses seemed to be more meaningful. The median survival for all 52 = was=20 5.6 months. The authors were unable to conclude the superiority of = one=20 regimen over the other [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec30></A> <DIV class=3DHeading3>Retrospective case series</DIV> <P class=3D"">The last class III study qualifying for inclusion in this = guideline=20 was a simple retrospective case series of 35 patients, all treated with = TMZ=20 (200 mg/m<SUP>2</SUP> for 5 days every 28 days) with 12 = receiving=20 stereotactic radiosurgery and with ten receiving WBRT. Median survival = was=20 8 months with one complete response and two partial responses = observed; the=20 longest duration being 16 months. The authors concluded the results = were=20 =93favorable=94 but appropriately did not attempt to compare the groups = for=20 superiority [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR45">45</A></CITE>].=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec31></A> <HR> <DIV class=3Dheading2>Fotemustine</DIV> <P class=3D"">The use of fotemustine was addressed in six studies, one = of which=20 was evidence class I [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>]=20 and five of which were evidence class III [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>].=20 Five of the six included only brain metastases from melanoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>].=20 </P> <DIV class=3D""><A name=3DSec32></A> <DIV class=3DHeading3>Randomized controlled study</DIV> <P class=3D"">The study by Mornex et al., was a randomized controlled = study of 76=20 individuals with brain metastases from melanoma yielding class I data. = Group 1=20 received fotemustine intravenously at a dose of = 100 mg/m<SUP>2</SUP> on=20 days 1, 8, and 15 followed by a 5 week rest period followed by a = single=20 dose every 3 weeks thereafter. Group 2 received the same dosage = regimen of=20 fotemustine with the addition of WBRT at a dose 37.5 Gy delivered = in 15=20 fractions over 3 consecutive weeks. Gender, age, extent of systemic = disease, and=20 number of intracranial metastases were balanced. The performance status = of group=20 2 was significantly better than in group 1 = (<I>p</I> =3D 0.019).=20 Utilizing intent to treat analysis there was no difference in survival, = response=20 rate (complete responses combined with partial responses) or tumor = control=20 (defined as complete responses combined with partial responses and = stable=20 disease) between the two groups. Median time to cerebral progression was = longer=20 in the patients treated with both being 49 days in group 1 and = 80 days=20 in group 2 (<I>p</I> =3D 0.069) [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>].=20 No newer studies of fotemustine in this patient group have met criteria = for=20 inclusion in this guideline. </P></DIV> <DIV class=3D""><A name=3DSec33></A> <DIV class=3DHeading3>Prospective single armed phase II studies</DIV> <P class=3D"">In the class III studies an array of uses of this therapy = and=20 subsequent outcomes can be found. In one study using fotemustine alone = for brain=20 metastases from melanoma Jacquilat et al., described 39 individuals who = had a=20 median survival of 26 weeks from initiation of therapy. There were = two=20 complete responses and nine partial responses with the median duration = of=20 response being 11 weeks. The promising nature of this study, = published=20 prior to the other studies meeting criteria for inclusion in this = guideline,=20 likely spurred the additional investigations that have been noted = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>].=20 Brocker et al., reported the use of WBRT and fotemustine in 13 patients = with=20 melanoma brain metastases not amenable to surgery or stereotactic = radiotherapy,=20 with seven achieving partial response or stable disease. Among those = seven=20 median survival was 6 months and survival in the rest was = 2 months=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>].=20 In a somewhat larger study Chang et al., combined fotemustine with = dacarbazine=20 in a group of 34 patients with brain metastases from melanoma whose = median=20 survival was 4.5 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>].=20 Cotto et al., reported a series of 31 individuals with brain metastases = from=20 NSCLC treated with fotemustine plus cisplatin. Twenty-five cases were = evaluable=20 for response with two achieving complete response and two achieving = partial=20 response. Median survival was reported as 16 weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR62">62</A></CITE>].=20 Hematologic toxicity in both the Chang and the Cotto studies was in = excess of=20 that seen with the use of fotemustine alone as noted by Jacquilat = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec34></A> <DIV class=3DHeading3>Case series</DIV> <P class=3D"">Ulrich et al., reported their case series of 12 patients = with brain=20 metastases from melanoma who were treated with induction therapy of = fotemustine=20 at 100 mg/m=B2 once a week with simultaneous WBRT to a total dose = ranging=20 from 32 to 58 Gy followed by maintenance treatment with = 100 mg/m=B2=20 fotemustine every 4 weeks thereafter. Two of the 12 individuals = received=20 dacarbazine 200 mg/m<SUP>2</SUP> on days 3 and 5 of the first = 2 weeks.=20 Six individuals had complete or partial intracranial remission and = amongst those=20 the mean survival was 8.2 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>].=20 Grade 3 or 4 thrombocytopenia was seen in four cases and grade 3 or 4 = leukopenia=20 was seen in four cases. The variation in radiation doses and systemic=20 chemotherapy (16% of cases receiving dacarbazine) results in the data = from this=20 publication being classified as class III. </P></DIV></DIV> <DIV class=3D""><A name=3DSec35></A> <HR> <DIV class=3Dheading2>Chemotherapy agent summary</DIV> <P class=3D"">Although class I, II and III data could be discerned from = the=20 literature regarding the use of TMZ and fotemustine in the treatment of = brain=20 metastases, meaningful survival benefit could only be demonstrated when=20 subjected to rigorous analysis in patients with melanoma metastases when = added=20 to WBRT. There were numerous reports of individuals who benefited in one = form or=20 another from the use of these agents and it cannot be concluded that = there might=20 not be a specific circumstance where TMZ or fotemustine are of value in = the=20 therapy of brain metastases. To improve this situation, investigations = of these=20 and other systemically administered agents is clearly warranted. </P> <DIV class=3D""><A name=3DSec36></A> <DIV class=3DHeading3>Molecular targeted agents</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided six unique studies = that met the=20 criteria for support of guidelines recommendations regarding the use of=20 molecular targeted agents in the management of brain metastases = (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab5">5</A>).<A=20 name=3DTab5></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 5 </SPAN>Summary = of molecular=20 targeted agents </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author(year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">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"">Tumor response</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"">Gefitinib</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ceresoli [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR71">71</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 10%</P> <P class=3D"">(CR 0/41; PR 4/41)</P> <P class=3D"">Stable disease: 7/41</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 3 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Chiu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR72">72</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 21 for BM = sub-group) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">NR for BM sub-group</P></TD> <TD align=3Dleft> <P class=3D"">Of 8 pts with measurable BM</P> <P class=3D"">Objective response in brain: 50%</P> <P class=3D"">(CR 0/8; PR 4/8)</P> <P class=3D"">(Stable disease 3/8</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: = 3.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hotta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 14 for BM = sub-group) </P></TD> <TD align=3Dleft> <P class=3D"">NSCLC; data extracted for BM sub-group</P></TD> <TD align=3Dleft> <P class=3D"">NR for BM subgroup</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 43%</P> <P class=3D"">(CR 1/14, PR 5/14)</P> <P class=3D"">Stable disease 8/14</P> <P class=3D"">Objective response at extra-cranial sites: = 7/14</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Namba [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR69">69</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 15) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">8.3 months</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 60%</P> <P class=3D"">(CR 1/15; PR 8/15)</P> <P class=3D"">Stable disease 2/15</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shimato [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR70">70</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 8) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 5/8 pts</P> <P class=3D"">Of the 5 pts with an objective response:</P> <P class=3D"">3 pts classified as effective with gefitinib as = response was=20 in the setting of an uncontrollable BM or new BM after = radiotherapy</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Wu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 40) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC sub-type adenocarinoma</P></TD> <TD align=3Dleft> <P class=3D"">15 months</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 38%</P> <P class=3D"">(CR 1/40; PR14/40)</P> <P class=3D"">Stable disease 18/40</P> <P class=3D"">Progressive disease 7/40</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival:=20 9.0 months</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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>LR</I> Local recurrence at original site in = brain,=20 <I>MGd</I> Motexafin-gadolinium, <I>NR</I> Not reported, <I>NS</I> Not=20 significant, <I>NSCLC</I> Non-small cell lung cancer, <I>OR</I> = Objective=20 response, <I>PR</I> Partial response, <I>Pts</I> Patients, <I>RCT</I> = Randomized=20 control trial, <I>SRS</I> Stereotactic radiosurgery, <I>TMZ</I> = Temozolomide,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV></DIV></DIV></DIV> <P class=3D"">There is only class III evidence that a molecular targeted = agent,=20 gefitinib, results in partial response or stable disease in = approximately 80=9690%=20 of patients with brain metastases due to NSCLC. </P> <P class=3D"">Recent advances in the treatment of many malignancies have = frequently been due to the incorporation of molecular targeted agents = into the=20 treatment regimen. In NSCLC the two categories of molecular targeted = agents that=20 have received the most attention are agents targeting the epidermal = growth=20 factor or angiogenesis pathways [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR65">65</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR66">66</A></CITE>].=20 The use of RECIST criteria [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR67">67</A></CITE>]=20 to measure tumor response to these agents likely underestimates their=20 effectiveness since prolonged tumor stabilization has been noted with = these=20 agents. </P></DIV> <DIV class=3D""><A name=3DSec37></A> <DIV class=3DHeading3>Epidermal growth factor inhibiting agents</DIV> <P class=3D"">Gefitinib inhibits numerous tyrosine kinases, including = the=20 epidermal growth factor receptor (EGFR). It can be given orally and was = approved=20 for use in advanced NSCLC. Erlotinib is another widely used tyrosine = kinase=20 inhibitor of the EGFR receptor. Cetuximab is a monoclonal antibody to = the EGFR=20 receptor and is currently being evaluated in locally advanced and = advanced=20 NSCLC. </P> <P class=3D"">Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab5">5</A>=20 summarizes the case reports [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR70">70</A></CITE>]=20 and small single arm prospective studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR71">71</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>]=20 of gefitinib for patients with brain metastases from NSCLC. Most of = these have=20 demonstrated tumor response or stabilization in the majority of the = patients=20 treated. However, it is not generally used in patients as first line = treatment=20 for symptomatic brain metastases and there is no evidence that it should = be used=20 instead of WBRT or other conventional treatments [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>].=20 </P> <P class=3D"">An area of ongoing research is in the predictive value of = EGFR=20 mutations in NSCLC [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR74">74</A></CITE>].=20 In eight patients with brain metastases from lung cancer, Shimato et = al.,=20 reported the association of EGFR mutations with a higher rate of tumor=20 response/stabilization with gefitinib in a small number of patients. = Most of=20 these patients had previously undergone WBRT and this complicated the=20 attribution of tumor response or stabilization to gefitinib alone = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR70">70</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec38></A> <DIV class=3DHeading3>Angiogenic-inhibiting agents</DIV> <P class=3D"">Agents targeting the angiogenesis pathway include = thalidomide and=20 bevacizumab. Bevacizumab is a monoclonal antibody against vascular = epidermal=20 growth factor receptor (VEGFR). Elevated VEGFR has been linked with = development=20 of brain metastases in murine models of NSCLC [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR75">75</A></CITE>].=20 There are no prospective studies of anti-angiogenesis agents for brain=20 metastases in humans in part due to concern regarding the possibility of = treatment-related intracranial bleeding. Prospective studies that have = shown a=20 survival benefit with bevacizumab in patients with non-squamous NSCLC = excluded=20 patients with known brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR76">76</A></CITE>].=20 A recently presented study by Akerly et al., concluded that the use of=20 bevacizumab along with cytotoxic chemotherapy agents resulted in only = one=20 central nervous system hemorrhage in a group of 85 patients with = non-small cell=20 carcinoma and known brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR77">77</A></CITE>].=20 More studies have been proposed to evaluate the safety of bevacizumab in = patients with brain metastases who undergo WBRT but no data meeting the = criteria=20 for inclusion in a recommendation are available. </P></DIV></DIV> <DIV class=3D""><A name=3DSec39></A> <HR> <DIV class=3Dheading2>Molecular targeted agent summary</DIV> <P class=3D"">The molecular underpinnings of tumor growth are better = understood=20 than ever in the past, but translation of this information to the = treatment of=20 brain metastases has not yet resulted in robust improvement in treatment = outcome=20 parameters. Isolated cases of treatment response have been observed with = epidermal growth factor inhibiting agents and angiogenic-inhibiting = agents. By=20 no means should agents related to epidermal growth factor or vascular=20 endothelial growth factor be viewed as the only candidates for the = targeted=20 therapies of brain metastases. Larger prospective and comparative = studies,=20 likely combined with more standard therapies, will be necessary to = determine if=20 such targeted agents will really contribute to tumor control and = improved=20 survival. </P></DIV> <DIV class=3D""><A name=3DSec40></A> <HR> <DIV class=3Dheading2>Investigational therapy summary</DIV> <P class=3D"">Not surprisingly, the clinical work done thus far with = newer=20 treatment modalities for metastatic brain tumors has not provided data = that=20 immediately translates into level 1 recommendations. Some progress has = been made=20 in defining the roll of TMZ in the management of brain metastases and it = is=20 clear that though there is a role it is limited as noted in the level 2=20 recommendation provided. Much of the clinical investigative work = completed and=20 published simply defines new problems and challenges with the techniques = and=20 agents that can be addressed in studies with properly asked questions. = Thus,=20 investigations to improve upon weaknesses identified in the above = discussion=20 continue to be reported. For example, demonstration of ongoing research = activity=20 for molecular targeted agents such as the assessment of gefitinib = efficacy, as=20 well as on a number of other fronts, is evidenced through reports at = national=20 meetings [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR78">78</A></CITE>].=20 Even when no specific positive level 1 recommendations can be made, it = is still=20 appropriate to encourage enrollment in properly designed and conducted = clinical=20 trials of new treatment modalities and agents. </P></DIV> <DIV class=3D""><A name=3DSec41></A> <HR> <DIV class=3Dheading2>Key issues for future investigation</DIV> <P class=3D"">New modalities in the therapy of metastatic brain tumors = need not be=20 limited to the radiation therapy, radiation sensitizers, chemotherapy = and=20 molecular targeted agents mentioned in this guideline. Assessment of = alternative=20 types of radiation, improved radiation planning systems, improved = radiation and=20 chemotherapy targeting systems and assessment of other tumor metabolic = pathways=20 for targeting are critical to making progress against this broad ranging = disease. Enrollment of patients in properly conducted studies of each of = these=20 agents and modalities is warranted in order to learn their true value. = </P> <P class=3D"">Use of nanoparticle technology for identifying tumors, = targeting=20 therapy and assessing response early in therapy warrants particular = attention.=20 Investigation of other methods of molecular imaging, for instance with = MRI or=20 positron emission tomography, may result in better methods of early = detection of=20 therapeutic efficacy or failure helping to minimize time wasted on = ineffective=20 treatments. Improved radiation and systemic treatment planning and = targeting may=20 decrease toxicity to normal cerebral tissue improving quality of life = even=20 though disease control may not be impacted. </P> <P class=3D"">An exhaustive list of biologic issues that should be = addressed in=20 the therapy of cerebral metastases cannot be provided here but the = following=20 highlights should serve as inspiration to motivated investigators. = Though EGFR=20 and VEGFR are recognized as being important in many tumor types, they = are but=20 one avenue by which disordered molecular signaling provides = proliferative=20 advantage. Metastatic tumor cell resistance to standard alkylating = agents is yet=20 to be addressed effectively, especially in the central nervous system. = The=20 importance of tumor stem cells in metastatic brain lesions has yet to be = defined=20 in detail. Though the blood brain barrier is not generally an issue in = larger=20 brain metastases, the possibility of smaller clusters of cells with = growth=20 potential being shielded from therapy by this structure must be = investigated.=20 </P> <P class=3D"">The following is a list of major ongoing or recently = closed=20 randomized clinical trials pertaining to the use of emerging therapies = that=20 evaluate treatment comparisons addressed by this guideline paper for the = management of brain metastases. </P> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>Temozolomide for Treatment of Brain Metastases From Non-Small = Cell=20 Lung Cancer (Study P03247AM3) (COMPLETED)=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Randomized, Open-Label = Phase 2=20 Study of Temozolomide Added to Whole Brain Radiation Therapy = Versus Whole=20 Brain Radiation Therapy Alone for the Treatment of Brain = Metastasis From=20 Non-Small Cell Lung Cancer </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>: NCT00076856=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Not provided = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Not provided </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Schering-Plough = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>Study of Temozolomide in the Treatment of Brain Metastasis From=20 Non-Small-Cell Lung Cancer (Study P02143) (COMPLETED)=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase II Study of = Temozolomide (SCH=20 52365) in Subjects with Brain Metastasis from Non-Small-Cell Lung = Cancer=20 </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> NCT00034697=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Not provided = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Not provided </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Schering-Plough = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>Safety and Tolerability of Low-Dose Temozolomide During Whole = Brain=20 Radiation in Patients With Cerebral Metastases From Non-Small-Cell = Lung=20 Cancer (Study P04071) (TERMINATED)=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Randomized Phase II Study:=20 Temozolomide (TMZ) Concomitant to Radiotherapy Followed by = Sequential TMZ=20 in Advanced NSCLC Patients With CNS Metastasis Versus Radiotherapy = Alone=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Terminated (Phase II) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00266812=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Not provided = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Not provided </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> = Schering-Plough, AESCA=20 Pharma GmbH </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>Radiation Therapy With or Without Temozolomide in Treating = Patients=20 With Non-Small Cell Lung Cancer That is Metastatic to the Brain=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase II Study Of = Temozolomide (SCH=20 52365) In Subjects With Brain Metastasis From Nonsmall Cell Lung = Cancer=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Active, not recruiting (Phase II)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00030836=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Lauren E. Abrey, = MD, Memorial=20 Sloan-Kettering 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> Memorial = Sloan-Kettering=20 Cancer Center, National Cancer Institute (NCI) = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>Temozolomide With or Without Radiation Therapy to the Brain in=20 Treating Patients With Stage IV Melanoma That Is Metastatic to the = Brain=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Temozolomide Versus=20 Temozolomide + Whole Brain Radiation In Stage IV = Melanoma=20 Patients With Asymptomatic 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> NCT00020839=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Juergen C. Becker, = MD, PhD=20 Universitaets-Hautklinik Wuerzburg </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 </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>6. </TD> <TD>Radiation Therapy Combined With Either Gefitinib or Temozolomide = in=20 Treating Patients With Non-Small Cell Lung Cancer and Brain = Metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Whole Brain Radiotherapy in = Combination With Gefitinib (Iressa) or Temozolomide (Temodal) for = Brain=20 Metastases From Non-Small Lung Cancer (NSCLC) A Randomized Phase = II Trial=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Recruiting (Phase II) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00238251=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> Study Chair: = Gianfranco=20 Pesce, MD Oncology Institute of Southern Switzerland </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Investigator:</B> Roger Stupp, MD Centre = Hospitalier=20 Universitaire Vaudois </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Switzerland </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Swiss Group for = Clinical=20 Cancer Research </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>7. </TD> <TD>Radiation Therapy and Stereotactic Radiosurgery With or Without=20 Temozolomide or Erlotinib in Treating Patients With Brain = Metastases=20 Secondary to Non-Small Cell Lung Cancer=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase III Trial Comparing = Whole=20 Brain Radiation And Stereotactic Radiosurgery Alone Versus With=20 Temozolomide Or Erlotinib In Patients With Non-Small Cell Lung = Cancer And=20 1=963 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> NCT00096265=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Paul Sperduto, MD, MAPP Park Nicollet Cancer=20 Center</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Minesh P. Mehta, MD University of Wisconsin,=20 Madison</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">H. I. Robins, MD, PhD University of Wisconsin,=20 Madison</DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States and Canada (56 = locations)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Radiation = Therapy=20 Oncology Group, National Cancer Institute (NCI) = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>8. </TD> <TD>Comparison Study of WBRT and SRS Alone Versus With Temozolomide = or=20 Erlotinib in Patients With Brain Metastases of NSCLC=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase III Trial Comparing = Whole=20 Brain Radiation (WBRT) and Stereotactic Radiosurgery (SRS) Alone = Versus=20 With Temozolomide or Erlotinib in Patients With Non-Small Cell = Lung Cancer=20 and 1=963 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> NCT00268684=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Felix Bokstein, = M.D. Tel-Aviv=20 Sourasky Medical Center </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Israel </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Tel-Aviv = Sourasky Medical=20 Center, RTOG = </DIV></DIV></TD></TR></TBODY></TABLE></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. The = editorial=20 assistance of Emily Feinstein is appreciated.</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>Robinson PD, Kalkanis SN, Linskey ME, = Santaguida PL=20 (2009) Methodology used to develop the AANS/CNS management of = brain=20 metastases evidence-based clinical practice parameter guidelines. = J=20 Neurooncol. doi:<A=20 = href=3D"http://dx.doi.org/10.1007/s11060-009-0059-2">10.1007/s11060-009-0= 059-2</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Centre for Evidence-Based Physiotherapy (2009) = Physiotherapy evidence database (PEDro). <A=20 href=3D"http://www.pedro.org.au/">http://www.pedro.org.au/</A>. = Accessed Jan=20 2009 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>3.</TD> <TD><A name=3DCR3></A>Maher CG, Sherrington C, Herbert RD, Moseley = AM,=20 Elkins M (2003) Reliability of the PEDro scale for rating quality = of=20 randomized controlled trials. 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From: Subject: 10.1007/s11060-009-0058-3 Date: Fri, 18 Dec 2009 19:08:38 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0022_01CA8015.81A56850" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0022_01CA8015.81A56850 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/vw55868761322267/fulltext.html 10.1007/s11060-009-0058-3</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/s11060-009-0058-3</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of emerging and = investigational=20 therapies for metastatic brain tumors: a systematic review and = evidence-based=20 clinical practice guideline of selected topics </DIV> <P class=3DAuthorGroup>Jeffrey J. Olson<SUP>1</SUP>,=20 Nina A. Paleologos<SUP>2</SUP>,=20 Laurie E. Gaspar<SUP>3</SUP>, = Paula D. Robinson<SUP>4</SUP>,=20 Rachel E. Morris<SUP>4</SUP>, Mario Ammirati<SUP>5</SUP>, = David W. Andrews<SUP>6</SUP>, = Anthony L. Asher<SUP>7</SUP>,=20 Stuart H. Burri<SUP>8</SUP>, = Charles S. Cobbs<SUP>9</SUP>,=20 Douglas Kondziolka<SUP>10</SUP>, = Mark E. Linskey<SUP>11</SUP>,=20 Jay S. Loeffler<SUP>12</SUP>, = Michael McDermott<SUP>13</SUP>,=20 Minesh P. Mehta<SUP>14</SUP>, Tom Mikkelsen<SUP>15</SUP>, = Roy A. Patchell<SUP>16</SUP>, = Timothy C. Ryken<SUP>17</SUP>=20 and Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#ContactOfAuthor19"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/vw55868761322267/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, 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=3DAff2></A>(2) </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=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = University=20 of Colorado-Denver, Denver, CO, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>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=3DAff5></A>(5) </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=3DAff6></A>(6) </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=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Carolina=20 Neurosurgery and Spine Associates, Charlotte, NC,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = Carolinas=20 Medical Center, Charlotte, NC, = 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 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=3DAff10></A>(10) </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=3DAff11></A>(11) </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=3DAff12></A>(12) </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=3DAff13></A>(13) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff14></A>(14) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Human Oncology, = University of=20 Wisconsin School of Public Health and Medicine, Madison, WI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Henry Ford = Health=20 System, Detroit, MI, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff16></A>(16) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff17></A>(17) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Iowa Spine = and=20 Brain Institute, Iowa City, IA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff18></A>(18) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Henry Ford = Health=20 System, Hermelin Brain Tumor Center, 2799 West Grand Blvd, K-11, = Detroit,=20 MI 48202, USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor19></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/vw55868761322267/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>8 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B> </SPAN>What evidence is = available=20 regarding the emerging and investigational therapies for the treatment = of=20 metastatic brain tumors?=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 brain=20 metastases.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>New radiation sensitizers</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> A subgroup analysis of a large = prospective=20 randomized controlled trial (RCT) suggested a prolongation of time to=20 neurological progression with the early use of motexafin-gadolinium = (MGd).=20 Nonetheless this was not borne out in the overall study population and = therefore=20 an unequivocal recommendation to use the currently available radiation=20 sensitizers, motexafin-gadolinium and efaproxiral (RSR 13) cannot be = provided.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Interstitial modalities</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">There is no evidence to support the routine use of new = or existing=20 interstitial radiation, interstitial chemotherapy and or other = interstitial=20 modalities outside of approved clinical trials. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>New chemotherapeutic agents</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 2</I> Treatment of melanoma brain metastases = with whole=20 brain radiation therapy and temozolomide is reasonable based on one = class II=20 study. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Depending on individual circumstances = there may be=20 patients who benefit from the use of temozolomide or fotemustine in the = therapy=20 of their brain metastases. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Molecular targeted agents</I></B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> The use of epidermal growth factor = receptor=20 inhibitors may be of use in the management of brain metastases from = non-small=20 cell lung carcinoma. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Radiation sensitizers - Interstitial=20 modalities - New chemotherapeutic agents - Molecular = targeted agents - Anti-angiogenesis = agents - Systematic=20 review - Practice guideline </P> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">As can be gleaned by the data collected and the questions = assessed=20 in the other papers in this guideline series, uniformly successful = control of=20 brain metastases has not been achieved. Even in those selected cases of=20 outstanding control, toxicity from the treatment itself can result in an = overall=20 decrement in the person=92s level of function. Fortunately there is = research=20 proceeding on a number of fronts to improve this situation. To provide = some=20 insight into these investigative areas, modalities that have reached the = point=20 of assessment by clinical trials warrant critical review. </P> <P class=3D"">The objectives of this paper are to assess both = comparative and=20 non-comparative studies of the following therapies that are still in the = investigational stage (i.e., not currently available outside of clinical = trials). This will include (1) the radiation sensitizers = motexafin-gadolinium=20 and RSR 13, (2) local modalities placed at the time of surgical excision = including local irradiation with the balloon-based brachytherapy,=20 stereotactically placed radiation sources, and local chemotherapy with=20 BCNU-impregnated polymers, (3) the role of the chemotherapeutic agents=20 temozolomide and fotemustine, and (4) the molecular targeted agents = against=20 epidermal growth factor or angiogenic receptors. </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. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR1">1</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"">For literature to be included for consideration in = creation of the=20 guidelines related to this question, it needed to meet the following = criteria:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Include patients with brain metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Arise from fully-published primary studies with a publication = date of=20 1990 forward or abstracts from the 2006=962008 meetings of AANS, = CNS, SNO,=20 ASTRO, ASCO and the AANS/CNS joint section on tumors satellite = symposiums=20 (all study designs for primary data collection were included; = e.g.,=20 randomized controlled trials, non-randomized trials, cohort = studies,=20 case=96control studies, or case series). </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Evaluation of one or more or the following modalities was = necessary:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Radiation sensitizers:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Motexafin-gadolinium</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Efaproxiral (RSR=20 13)</TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Local modalities placed at the time of surgical excision or = biopsy:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Local irradiation=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Balloon tipped catheter placement</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> = </TD> <TD>Interstitial radiosurgery or brachytherapy (without=20 hyperthermia)</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Local chemotherapy to the resection=20 cavity</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>New chemotherapeutic agents: temozolomide or fotemustine=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Molecular targeted agents: Gefitinib (ZD1839)</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Anti-angiogenesis agents: Bevacizumab=20 (Avastin)</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>The number of study participants with brain metastases needed to = be=20 >5 per study arm for at least two of the study arms for = comparative=20 studies and >5 overall for non-comparative studies. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>The following criteria was applied to full-length papers, but = not=20 meeting abstracts: For studies evaluating interventions = exclusively in=20 patients with brain metastases, the baseline characteristics of = study=20 participants needed to be provided by treatment group for = comparative=20 designs and overall for non-comparative studies. For studies with = mixed=20 populations (i.e., includes participants with conditions other = than brain=20 metastases), baseline characteristics needed to be provided for = the=20 sub-group of participants with brain metastases, and stratified by = treatment group for comparative studies.=20 </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Study selection and quality assessment</DIV> <P class=3D"">Two independent reviewers evaluated citations using a = priori=20 criteria for relevance and documented decisions in standardized forms. = Cases of=20 disagreement were resolved by a third reviewer. The same methodology was = used=20 for full text screening of potentially relevant papers. Studies which = met the=20 eligibility criteria were data extracted by one reviewer and the = extracted=20 information was checked by a second reviewer. The PEDro scale [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR3">3</A></CITE>]=20 was used to rate the quality of randomized trials. The quality of = comparative=20 studies using non-randomized designs was evaluated using eight items = selected=20 and modified from existing scales. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper accompanying this = guideline=20 series. </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of questions to be answered regarding the practice=20 guidelines on the management of brain metastases based on a systematic = review of=20 the literature conducted in collaboration with methodologists at the = McMaster=20 University Evidence-based Practice Center. </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">Overall, 59 publications (53 primary studies and 6 = companion=20 papers) met the eligibility criteria for use in the discussion of the = scientific=20 foundation of this guideline (Fig. <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Fig1">1</A>).=20 A summary of the class of evidence of all the primary studies discussed = in this=20 scientific foundation are presented in Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab1">1</A>.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_58_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/vw55868761322267/MediaObjects/= 11060_2009_58_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> <A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>The = evidence class=20 provided by the included primary studies </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Description of evidence class</P></TH> <TH align=3Dleft> <P class=3D"">Class of evidence provided by included primary=20 studies</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">New radiation sensitizers: motexafin-gadolinium and=20 efaproxiral</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class I</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">3 RCTs: Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>],=20 Suh [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR5">5</A></CITE>],=20 Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">1 Prospective cohort study with historical controls: = Shaw=20 [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1 Prospective single arm study: Carde [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">Interstitial modalities</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class I</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">1 Retrospective cohort study: Ostertag [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D3> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D3> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">3 Prospective single arm studies:</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Ewend [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>],=20 Rogers [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>],=20 Nakagawa [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">7 Case series: Alesch [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>],=20 Bernstein [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>],=20 Bogart [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>],=20 Dagnew [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>],=20 Schulder [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>],=20 Curry [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>],=20 Nakamura [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">New chemotherapeutic agents: Temozolomide or=20 fotemustine</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Class I</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">1 RCT: Mornex [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2 Randomized phase II trials: Antonadou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>],=20 Verger [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">2 Retrospective cohort studies: Conill [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>],=20 Panagiotou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D4> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D4> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">22 Prospective single arm studies: Abrey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>],=20 Addeo [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>],=20 Agarwala [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>],=20 Caraglia [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>],=20 Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>],=20 Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>],=20 Cortot [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>],=20 Giorgio [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>],=20 Hwu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>],=20 Iwamoto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>],=20 Janinis [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR48">48</A></CITE>],=20 Kouvaris [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>],=20 Krown [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>],=20 Larkin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>],=20 Margolin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>],=20 Omuro [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>],=20 Rivera [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>],=20 Schadendorf [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>],=20 Brocker [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>],=20 Chang [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>],=20 Cotto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR62">62</A></CITE>],=20 Jacquilat [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2 Case series: Hofmann [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR45">45</A></CITE>],=20 Ulrich [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2 Sub-group analyses of prospective studies: = Bafaloukos=20 (2006),</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Boogerd [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D3> <P class=3D"">Molecular targeted agent: Gefitinib (ZD = 1839)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class I</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by one or more well-designed = randomized=20 controlled clinical trials, including overview (meta-analyses) of = such=20 trials </P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Class II</P></TD> <TD align=3Dleft> <P class=3D"">Evidence provided by well-designed observational = studies with=20 concurrent controls (e.g. case control and cohort = studies)</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft rowSpan=3D2> <P class=3D""> Class III</P></TD> <TD align=3Dleft rowSpan=3D2> <P class=3D"">Evidence provided by expert opinion, case series, = case reports=20 and studies with historical controls</P></TD> <TD align=3Dleft> <P class=3D"">3 Prospective single arm studies: Ceresoli [<CITE><A = = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR71">71</A></CITE>],=20 Chiu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR72">72</A></CITE>],=20 Wu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>]=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">3 Case series: Hotta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>],=20 Namba [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR69">69</A></CITE>],=20 Shimato [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">70</A></CITE>]=20 </P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D"">Fully published papers. Conference proceeding abstracts = not=20 included</DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>New radiation sensitizers</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided five unique studies = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>]=20 and five companion papers [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR9">9</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR13">13</A></CITE>]=20 that met the criteria for support of guidelines recommendations = regarding the=20 use of new radiation sensitizers in the management of brain metastases=20 (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab2">2</A>).<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 2 </SPAN>Summary = of primary=20 radiation sensitizer 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/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"">Tumor response</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"">Motexafin-gadolinium</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Carde [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase Ib/II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + MGd (phase Ib = <I>n</I> =3D 39; phase=20 II <I>n</I> =3D 22) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">4.7 months (Phase 1b + phase = II)</P></TD> <TD align=3Dleft> <P class=3D"">Radiographic response in brain:</P> <P class=3D"">Phase Ib (23 assessable pts):</P> <P class=3D"">CR 1/23, PR 13/23, SD 8/23, PD 1/23</P> <P class=3D"">Phase II (18 assessable pts):</P> <P class=3D"">CR 0/18, PR 13/18, SD 4/18, PD 1/18</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>]=20 (2003) </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 208) </P> <P class=3D"">G2: WBRT + MGd = (<I>n</I> =3D 193) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.9 months</P> <P class=3D"">G2: 5.2 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain (CR or PR):</P> <P class=3D"">G1: 50.7%</P> <P class=3D"">G2: 46.3% (<I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Median time to neurologic progression (by ERC):</P> <P class=3D"">G1: 8.3 months</P> <P class=3D"">G2 9.5 months (log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">Median time to neurologic progression (by = investigators):</P> <P class=3D"">G1: 3.8 months</P> <P class=3D"">G2 4.3 months (log-rank; = <I>p</I> =3D 0.018)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Mehta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>]=20 (2008) </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 275) </P> <P class=3D"">G2: WBRT + MGd = (<I>n</I> =3D 279) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 5.8 months</P> <P class=3D"">G2: 5.1 months (log-rank; = <I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Interval to neurologic progression:</P> <P class=3D"">G1: 10.0 months</P> <P class=3D"">G2: 15.4 months (Neurologic progression curves: = stratified log-rank; <I>p</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Efaproxiral (RSR 13)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shaw [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective cohort study with historical = controls</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT [historical controls]</P> <P class=3D"">(<I>n</I> =3D 1070) </P> <P class=3D"">G2: WBRT + efaproxiral</P> <P class=3D"">(<I>n</I> =3D 57 RPA class II) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.1 months</P> <P class=3D"">G2: 6.4 months (Survival curves: log-rank;=20 <I>p</I> =3D 0.0174) </P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">G1: Not reported</P> <P class=3D"">G2: CR 7/57, PR 13/57, SD 21/57</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Suh [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR5">5</A></CITE>]=20 (2006) </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 + supplemental O<SUB>2</SUB>=20 (<I>n</I> =3D 250) </P> <P class=3D"">G2: WBRT + supplemental=20 O<SUB>2</SUB> + efaproxiral (<I>n</I> =3D 265) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.4 months</P> <P class=3D"">G2: 5.4</P> <P class=3D"">months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">NSCLC/breast cancer sub-group:</P> <P class=3D"">G1: 4.4 months</P> <P class=3D"">G2: 6.0 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain (CR or PR):</P> <P class=3D"">G1: 96/250 (38%)</P> <P class=3D"">G2: 121/265 (46%) (<I>p</I> =3D NS) </P> <P class=3D"">Response rate in NSCLC/breast cancer sub-group:</P> <P class=3D"">G1: 41%</P> <P class=3D"">G2: 54% (<I>p</I> =3D 0.01) </P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival:</P> <P class=3D"">G1: 3.5 months</P> <P class=3D"">G2: 4.0 month (log-rank; = <I>p</I> =3D NS) </P> <P class=3D"">Median progression-free survival in NSCLC/breast = cancer=20 sub-group:</P> <P class=3D"">G1: 3.7 months</P> <P class=3D"">G2: 4.8 month (log-rank; = <I>p</I> =3D NS)=20 </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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>LR</I> Local recurrence at original site in = brain,=20 <I>MGd</I> Motexafin-gadolinium, <I>NR</I> Not reported, <I>NS</I> Not=20 significant, <I>NSCLC</I> Non-small cell lung cancer, <I>OR</I> = Objective=20 response, <I>PR</I> Partial response, <I>Pts</I> Patients, <I>RCT</I> = Randomized=20 control trial, <I>SRS</I> Stereotactic radiosurgery, <I>TMZ</I> = Temozolomide,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV></DIV></DIV></DIV> <P class=3D"">Many radiation sensitizers have been investigated to try = to increase=20 the effectiveness of whole-brain radiation therapy (WBRT). Two recent = radiation=20 sensitizers that have been extensively evaluated are motexafin = gadolinium and=20 efaproxiral. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Motexafin gadolinium</DIV> <P class=3D"">Motexafin gadolinium (MGd) is a metallotexaphrin that = localizes=20 within tumors in greater concentration than in normal tissues. This = agent is=20 detectable by magnetic resonance imaging (MRI) because it contains the=20 paramagnetic metal ion, gadolinium. Its exact mechanism of action is not = known=20 although it is known to be involved with electron scavenging. It may act = as both=20 a radiation sensitizer and modifier. </P> <P class=3D"">There is one prospective single arm study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>]=20 (class III evidence) and two randomized controlled studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>]=20 (class I evidence) evaluating MGd as a radiation sensitizer. Carde et = al.=20 published a prospective single arm phase Ib/II study which established = MGd=20 5 mg/kg given intravenously daily as the recommended best tolerated = dose=20 when combined with 30 Gy WBRT given in 10 fractions of 3 Gy. = This=20 yielded class III evidence regarding the feasibility and potential = efficacy of=20 MGd [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR7">7</A></CITE>].=20 </P> <P class=3D"">A subsequent randomized controlled study in 401 patients = with brain=20 metastases of various histologies, comparing WBRT alone versus WBRT with = motexafin gadolinium failed to show any significant difference in median = survival or tumor response [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR4">4</A></CITE>].=20 However, the median time to neurologic progression as determined by the=20 investigators was increased by 0.5 months = (<I>p</I> =3D 0.018) for=20 the group that received motexafin gadolinium. This effect was attributed = predominantly to the lung cancer stratum. Patients were stratified by = histology=20 (lung, breast or other) and a subset analysis revealed that the time to=20 neurological progression favored the MGd and WBRT arm for patients with = lung=20 cancer (median 5.5 months for MGd v 3.7 months for WBRT alone, = <I>p</I> =3D 0.025), but no difference was seen in the other = strata. A=20 companion study of neurocognitive function by Meyers et al. further = suggested=20 that MGd may preserve memory and executive function and prolong time to=20 neurocognitive and neurologic progression in patients with brain = metastases from=20 lung cancer [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR9">9</A></CITE>].=20 </P> <P class=3D"">An international phase III study was therefore conducted,=20 randomizing 554 patients with non-small cell lung carcinoma (NSCLC) to = WBRT=20 alone (30 Gy in 10 fractions) or to WBRT with MGd [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR6">6</A></CITE>].=20 The primary endpoint of the study was time to neurologic progression. = Although=20 time to neurological progression was improved in the MGd arm, it was not = a=20 statistically significant difference unless the patients enrolled = outside of=20 North America were excluded. In a subgroup analysis of the 348 North = American=20 patients, there was a statistically significant prolongation of time to=20 neurological progression from 8.8 to 24.2 months,=20 <I>p</I> =3D 0.04. This difference in outcome between the = North American=20 patients and patients treated elsewhere was attributed to the fact that = patients=20 in North America received the study treatment sooner after the diagnosis = of the=20 brain metastases. When WBRT was initiated within three weeks of = diagnosis of the=20 brain metastases, regardless of whether the patient was treated in North = America=20 or not, time to neurological progression was significantly prolonged by = the=20 addition of MGd (<I>p</I> =3D 0.006, HR =3D 0.59). A = major=20 reason for the delay to WBRT outside of North America was the use of=20 chemotherapy. This study failed to meet its primary objective of = increasing time=20 to neurologic progression and is considered a negative study. However = the=20 subgroup analysis mentioned, though post hoc and selective in nature, = can be=20 interpreted as providing class 2 evidence. </P></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Efaproxiral</DIV> <P class=3D"">Efaproxiral, (also known as RSR13; Allos Therapeutics, = Westminster,=20 CO) is an allosteric modifier of hemoglobin. Efaproxiral binds to = hemoglobin,=20 causing a change in its conformational structure, leading to a reduction = in=20 hemoglobin oxygen binding affinity. This leads to an increased release = of oxygen=20 into tissue, enhancing tumor oxygenation leading to radiation = sensitization.=20 Shaw et al. completed a phase II study in which 57 patients with brain=20 metastases received WBRT (30 Gy in 10 fractions of 3 Gy) with = daily=20 efaproxiral 50=96100 mg/kg. This yielded class III data showing = median=20 survival was 6.4 months which compared favorably to the Radiation = Therapy=20 Oncology Group=92s (RTOG) historical control patients (4.1 months) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR8">8</A></CITE>].=20 </P> <P class=3D"">This prompted a large phase III study of WBRT alone versus = WBRT with=20 efaproxiral in 515 patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR5">5</A></CITE>].=20 This study failed to reveal a significant difference in median survival, = tumor=20 response or median time to recurrence/progression with the addition of=20 efaproxiral although it prompted a confirmatory trial in patients with = brain=20 metastases related to breast cancer. The investigators found that = patients with=20 brain metastases related to breast cancer were more likely to receive at = least 7=20 of the planned 10 fractions of efaproxiral and were more likely to have = an=20 increased concentration of efaproxiral in red blood cells as compared to = patients with brain metastases due to other primary cancers such as lung = cancer=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR12">12</A></CITE>].=20 However, the confirmatory phase III study in breast cancer patients of = WBRT with=20 efaproxiral versus WBRT alone failed to demonstrate an improvement in = overall=20 survival or any other prespecified endpoint [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR14">14</A></CITE>].=20 </P> <P class=3D"">In summary, there is class I evidence that motexafin = gadolinium=20 (MGd) given daily during WBRT does not increase survival over survival = following=20 WBRT alone. Additionally, there is also class I evidence that = efaproxiral given=20 daily during WBRT does not increase survival over survival following = WBRT alone.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec12></A> <HR> <DIV class=3Dheading2>Radiation sensitizers summary</DIV> <P class=3D"">Considerable effort has been put into the development of = motexafin=20 gadolinium and efaproxiral yielding class I data supporting the = conclusion that=20 these agents do not improve the therapy of brain metastases. This is not = to say=20 that radiation sensitizers are without merit. The lessons learned in the = studies=20 reviewed here provide direction for further investigation and = encouraging=20 patient participation in such studies is warranted. </P></DIV> <DIV class=3D""><A name=3DSec13></A> <HR> <DIV class=3Dheading2>Interstitial modalities</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided 11 unique studies = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 and one companion study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR26">26</A></CITE>]=20 that met the criteria for support of guidelines recommendations = regarding the=20 use of interstitial modalities in the management of brain metastases=20 (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab3">3</A>).=20 In this discussion brachytherapy is defined as therapy placed inside of = or next=20 to the area being treated. Interstitial radiosurgery is defined here as=20 brachytherapy in which the therapy specifically consists of radiation.<A = name=3DTab3></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 3 </SPAN>Summary = of=20 interstitial modalities 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/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"">Tumor control</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"">Brachytherapy =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ostertag [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 (1995) </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: Temporary <SUP>125</SUP>Iseeds + WBRT=20 (<I>n</I> =3D 38) </P> <P class=3D"">G2: Temporary 125I seeds (<I>n</I> =3D 34) = </P> <P class=3D"">G3: Temporary <SUP>125</SUP>I seeds for recurrent BM = (<I>n</I> =3D 21) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 17 months</P> <P class=3D"">G2: 15 months</P> <P class=3D"">G3: 6 months</P> <P class=3D"">(Survival curves G1 vs. G2: Lee-Desu statistic;=20 <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR by treatment group</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Alesch [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Temporary <SUP>125</SUP>I seeds = (<I>n</I> =3D 19)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain (by CT scan):</P> <P class=3D"">Marked reduction 5/19</P> <P class=3D"">Slight reduction 11/19</P> <P class=3D"">Unchanged 2/19</P> <P class=3D"">Not evaluable 1/19</P> <P class=3D""># of pts with LR: 1/19</P> <P class=3D""># of pts with DR: 1/19</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bernstein [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>]=20 (1995) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Temporary high-activity <SUP>125</SUP>I seeds=20 (<I>n</I> =3D 10) </P></TD> <TD align=3Dleft> <P class=3D"">Single locally recurrent BM</P></TD> <TD align=3Dleft> <P class=3D"">46 weeks</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"">Surgery + brachytherapy</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bogart [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + permanent l<SUP>125</SUP>I seeds = (<I>n</I> =3D 15) </P></TD> <TD align=3Dleft> <P class=3D"">Single newly diagnosed BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">14 months</P></TD> <TD align=3Dleft> <P class=3D"">LR only: 2/15</P> <P class=3D"">DR only: 2/15</P> <P class=3D"">LR + DR: 1/15</P></TD> <TD align=3Dleft> <P class=3D"">Median time to BM recurrence: = 9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Dagnew [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + permanent <SUP>125</SUP>I seeds=20 (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft> <P class=3D"">Single newly diagnosed</P> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">17.8 months</P></TD> <TD align=3Dleft> <P class=3D""># of pts with local control: 25/26</P> <P class=3D""># of pts with DR: 10/26 (38%)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Rogers [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm Phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + GliaSite balloon catheter with=20 <SUP>125</SUP>I (<I>n</I> =3D 54) </P></TD> <TD align=3Dleft> <P class=3D"">Single newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">40 weeks</P></TD> <TD align=3Dleft> <P class=3D"">1 yr local control rate: 79%</P> <P class=3D"">1 yr distant brain control rate: 50%</P></TD> <TD align=3Dleft> <P class=3D"">Median time to distant brain recurrence:=20 54 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schulder [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>]=20 (1997) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + permanent <SUP>125</SUP>I seeds=20 (<I>n</I> =3D 13) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">7.6 months overall;</P> <P class=3D"">9 months if exclude two post-op deaths</P></TD> <TD align=3Dleft> <P class=3D""># of pts with local control: 9/11</P> <P class=3D""># of pts with DR: 7/11</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Surgery + local=20 chemotherapy =B1 WBRT</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ewend [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + carmustine polymer = wafers + WBRT=20 (<I>n</I> =3D 25) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed single BM</P></TD> <TD align=3Dleft> <P class=3D"">33 weeks</P></TD> <TD align=3Dleft> <P class=3D""># of pts with LR: 0/25 (0%)</P> <P class=3D""># of pts with DR: 4/25 (16%)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Nakagawa [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + FdUrd intracavitary chemotherapy = (<I>n</I> =3D 6 for BM sub-group) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain:</P> <P class=3D"">Complete response 3/6</P> <P class=3D"">No change 1/6</P> <P class=3D"">Progressive disease 2/6</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D"">Interstitial radiosurgery</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Curry [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Stereotatic interstitial radiosurgery with = photon</P> <P class=3D"">Radiosurgery system (<I>n</I> =3D 60) = </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">8 months</P></TD> <TD align=3Dleft> <P class=3D"">Of 59 evaluable BM; 13 BM not assessable</P> <P class=3D"">Lesion with local control: 48/59 (81%)</P> <P class=3D"">Lesions with progression: 11/59 (19%)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Nakamura [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Surgery + intra-operative radiation = therapy=20 (<I>n</I> =3D 43) </P></TD> <TD align=3Dleft> <P class=3D"">Single BM</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">1 yr survival rate: 53%</P></TD> <TD align=3Dleft> <P class=3D""># of pts with LR: 7/43</P> <P class=3D""># of pts with DR: 7/43</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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>KPS</I> Karnofsky performance score, <I>LR</I> = Local=20 recurrence at original site in brain, <I>MGd</I> Motexafin-gadolinium, = <I>NR</I>=20 Not reported, <I>NS</I> Not significant, <I>NSCLC</I> Non-small cell = lung=20 cancer, <I>OR</I> Objective response, <I>PR</I> Partial response, = <I>Pts</I>=20 Patients, <I>RCT</I> Randomized control trial, <I>SRS</I> Stereotactic=20 radiosurgery, <I>TMZ</I> Temozolomide, <I>WBRT</I> Whole-brain radiation = therapy=20 </DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec14></A> <DIV class=3DHeading3>Brachytherapy with or without whole brain = radiation=20 therapy</DIV> <P class=3D"">One retrospective series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 looking at three cohorts and two case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>]=20 met criteria for inclusion of their data in this portion of the = guideline. </P> <DIV class=3D""><A name=3DSec15></A> <H4 class=3DSection3>Retrospective multiple cohort series</H4> <P class=3D"">In a retrospective cohort study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>]=20 of the temporary implantation of <SUP>125</SUP>I seeds for spherical = brain=20 metastases (from a variety of primary sites) 4 cm or smaller in = diameter=20 Ostertag et al. looked at three groups of patients that the authors = refer to as=20 A, B and C, respectively, with A being temporary <SUP>125</SUP>I seeds = and WBRT=20 for patients with newly diagnosed brain metastases, B being temporary=20 <SUP>125</SUP>I seeds alone in patients newly diagnosed with brain = metastases,=20 and C being temporary <SUP>125</SUP>I seeds for patients with recurrent = brain=20 metastases treated with other modalities first. The chosen dose of = interstitial=20 radiation was 60 Gy prescribed to the rim of the lesion(s). The = dose of=20 WBRT was chosen to be 40 Gy in 2 Gy daily fractions. In terms = of=20 clinical characteristics, three cases with two lesions were treated in = the first=20 group, four cases with two lesions were treated in the second group and = twelve=20 cases with two lesions were treated in the third group. The groups were = balanced=20 except for age. The median age was 55 years, 58 years, and=20 47 years, by group, respectively, with a statistically significant = younger=20 age for the third group. Median survivals for the three groups were 17, = 15 and=20 6 months, respectively. The shorter survivals in those with = recurrent and=20 longer standing disease was not considered surprising. The difference = between=20 the first two brachytherapy groups (with or without WBRT, respectively) = was not=20 significant using Lee=96Desu statistic to assess the Kaplan=96Meier = survival curves.=20 The authors state that the temporary <SUP>125</SUP>I sources utilized in = the=20 manner outlined were not associated with radiation necrosis requiring = surgery in=20 any case. They go onto advocate =93interstitial radiosurgery=94 as a = method of=20 avoiding or postponing WBRT. The properly executed retrospective = comparison of=20 the cohorts treated here yielded class II evidence. However, the numbers = treated=20 in each group are moderate in nature and no comparison to metastatic = tumors=20 treated in a more standard method is provided. Thus, a level 2 = recommendation=20 cannot be provided [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR25">25</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec16></A> <H4 class=3DSection3>Case series</H4> <P class=3D"">In a case series of 19 patients, Alesch et al., describe = their use=20 of temporary <SUP>125</SUP>I seeds treating metastases from a variety of = primary=20 lesions with a tumor margin dose of 60 Gy. All but one case had one = lesion.=20 A mean dose rate of 11 cGy/hour (ranging from 5 to = 22 cGy/hour) was=20 used and the mean irradiation time before explantation was 28 days = (ranging=20 from 11 to 52 days). They utilized a simplistic plan with only one = catheter=20 per lesion. The authors point out the value of biopsy at the time of = implant to=20 rule out other processes, which excluded three cases from their series. = CT was=20 the predominant modality used for imaging and response assessment, = leaving the=20 possibility of other untreated small lesions open to question. The = responses=20 were classified as marked reduction (5 cases), slight reduction (11 = cases),=20 unchanged (2 cases) and not evaluable (1 case). Marked reduction versus = slight=20 reduction was not defined further. One patient had a temporary worsening = of an=20 existing hemiparesis. No patient died from neurologic causes. No mention = of=20 symptomatic radiation necrosis is provided. As this report is a case = series it=20 meets the criteria for class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>].=20 </P> <P class=3D"">In a small series of ten cases of single brain metastases = that had=20 recurred at the same site after surgical resection and WBRT Bernstein et = al.=20 describe the use of high activity <SUP>125</SUP>I seeds used to = administer=20 70 Gy or more at periphery of the lesion at a median dose rate of=20 67 cGy/h. Nine of the cases had lung primaries. The median time to = tumor=20 recurrence was 35 weeks. Median survival was 46 weeks. = Reoperation at=20 the implant site was necessary in three cases because of symptomatic = mass=20 effect, two for radiation necrosis and one for mixed tumor and radiation = necrosis. Two early deaths occurred from pulmonary emboli. The authors = point out=20 that the cases were highly selected and conclude that a more detailed = controlled=20 and randomized study compared to other therapies is necessary to assess = the real=20 value of this mode of therapy in brain metastases. This case series with = no=20 comparative component meets the criteria to provide class III evidence = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR19">19</A></CITE>].=20 This and the cases series by Alesch et al. support the feasibility of = this=20 modality but do not provide evidence of comparative efficacy necessary = to more=20 strongly support its recommendation [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR18">18</A></CITE>].=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec17></A> <DIV class=3DHeading3>Surgery and brachytherapy</DIV> <P class=3D"">One fully published single arm phase II study [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>]=20 and three case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>]=20 met criteria for inclusion of their data in this portion of the = guideline. </P> <DIV class=3D""><A name=3DSec18></A> <H4 class=3DSection3>Phase II single arm studies</H4> <P class=3D"">To look at the efficacy of the Gliasite Radiation Therapy = System=20 after surgical resection of single brain metastases Rogers et al. = designed a=20 phase II study. This system entails surgical placement of a balloon that = is=20 connected to a reservoir that is implanted subcutaneously. Liquid = containing=20 <SUP>125</SUP>I is then inserted postoperatively into the balloon by = injection=20 into the reservoir. Patients were required to have a single resected = lesion and=20 to have a Karnofsky performance score (KPS) of 70 or above. Fifty-four = cases=20 with tumors from a variety of primary sites were enrolled with a median = age of=20 60 and a median KPS of 90. The planned dose of radiation was 60 Gy = to a one=20 cm depth from the balloon surface. One year local control rate was the = primary=20 outcome assessed and was 79%. Distant brain control at the same interval = was 50%=20 with median time to development of those distant lesions being = 54 weeks.=20 Histologically confirmed radiation necrosis alone was observed in nine = cases and=20 in two others in combination with tumor recurrence. They estimated the = actuarial=20 1 year incidence of radiation necrosis without tumor at 23%. The = authors=20 made an attempt to assess functional status noting baseline median = Mini-Mental=20 Status Exam scores were 28.5. This remained stable at 29 at = 6 months and=20 12 months amongst the patients still surviving at those intervals.=20 Additionally the median FACT-BR score at baseline was 130 and at = 12 months=20 it was 112. Median survival was 40 weeks at the 1 year = follow-up point=20 of the report and only four of the 35 deaths that had occurred were due = to tumor=20 progression within the central nervous system and all were at sites not = treated=20 with the Gliasite. This data was obtained prospectively, but without = meaningful=20 concurrent comparative data rendering it class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>].=20 </P> <P class=3D"">Sills et al. provided a preliminary report captured in a = conference=20 proceeding search of a series of patients with one to three brain = metastases.=20 One lesion was treated with =93balloon brachytherapy=94 (presumably the = Gliasite=20 Radiation Therapy System) to a dose of 60 Gy at 5 mm and the = other=20 lesions treated with stereotactic radiosurgery. Of the 48 cases reported = (of a=20 planned enrollment of 50) one case had local recurrence at 3 months = and=20 another at 9 months. Radiation necrosis was confirmed surgically in = one=20 case 12 months after treatment and suspected by positron emission=20 tomography in another after 15 months. The primary outcome measures = planned=20 were 6 month and 1 year local control and this was not = reported. This=20 data was obtained prospectively, but is clearly incomplete and without=20 meaningful concurrent comparative data rendering it as class III = evidence=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR27">27</A></CITE>].=20 </P> <P class=3D"">In another preliminary report captured in a conference = proceeding=20 search, a study assessing radiation necrosis in brain metastases = patients by=20 Burri et al. provided a retrospective look in their practice database of = 20=20 cases that underwent resection followed by Gliasite implantation as = initial=20 primary therapy without WBRT. The chosen dose was 60 Gy though the = depth of=20 the dose is specified in only seven of the cases. Seven cases required = surgical=20 debridement of symptomatic progressive imaging changes that proved to be = radiation necrosis for a crude reoperation rate of 35%. They attempted = to=20 estimate an actuarial risk of reoperation in those with radiation = necrosis=20 noting it as 7% at 6 months reaching 84% at 24 months with a = median=20 time to that operation of 17 months. The authors conclude that = radiation=20 necrosis is a substantial risk with the use of the Gliasite device for = the dose=20 regimens they used for metastatic disease. The retrospective nature of = this=20 series is unable to filter for bias in case selection or nonsurgical = management=20 and provides no comparison to other modalities of radiation to determine = if=20 their findings are truly out of the ordinary for their practice. Thus = this case=20 series with limited clinical background and no comparative component = meets the=20 criteria to provide class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR28">28</A></CITE>].=20 The frequency of radiation necrosis with the use of Gliasite was = substantial in=20 the Rogers et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR16">16</A></CITE>]=20 and the Burri et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR28">28</A></CITE>]=20 studies. Additionally, the minimally described assessments for radiation = necrosis in the Sills et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR27">27</A></CITE>]=20 study results in the level 3 recommendation that this technique is best = utilized=20 in the clinical trial setting for metastatic brain tumors. </P></DIV> <DIV class=3D""><A name=3DSec19></A> <H4 class=3DSection3>Case series</H4> <P class=3D"">Bogart et al., report a series of 15 cases of solitary = metastases=20 from NSCLC treated with surgical resection and permanent <SUP>125</SUP>I = seeds=20 implanted on the surface of the tumor bed. Median KPS was 70 and ten of = the 15=20 individuals had the intracranial disease as the only active site. The = planned=20 dose was 5 cGy/h with estimated cumulative doses of = 80=96160 cGy to the=20 tumor bed [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR29">29</A></CITE>].=20 Median follow-up and survival was 14 months. The median time to = recurrence=20 was 9 months. Recurrences within the brain were local in 2 l, = distant=20 in two and both in one. One individual succumbed to an overwhelming = fungal=20 infection. None developed symptomatic radionecrosis. The authors = conclude that=20 this modality may be useful for selected patients but that further = studies in a=20 larger number of patients were warranted [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR20">20</A></CITE>].=20 </P> <P class=3D"">When looking at a series of 26 patients with single brain = metastasis=20 with very high performance status (median KPS 90) Dagnew et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>],=20 found a median actuarial survival of 17.8 months after surgical = resection=20 and placement of permanent low activity <SUP>125</SUP>I seeds with an = estimated=20 dose of 150 Gy to the tumor bed resection perimeter taking into = account=20 tumor cavity collapse. All cases reportedly had controlled systemic = disease from=20 a variety of primary sites. Only one patient had local recurrence and = only two=20 died of neurologic disease. Thirty-eight percent developed tumors = elsewhere in=20 the brain that on their review was higher than in patients who received = WBRT as=20 an initial part of their treatment (as previously seen in studies by = Noordijk et=20 al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR30">30</A></CITE>]=20 and Patchell et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR31">31</A></CITE>]).=20 One individual had deep venous thrombosis and pulmonary embolus = perioperatively.=20 Symptomatic radiation necrosis occurred in two individuals requiring = surgical=20 debridement. Both of those patients had tumors that had exceeded = 3 cm in=20 greatest diameter (3.1 and 5 cm). This case series with no = comparative=20 component meets the criteria to provide class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR21">21</A></CITE>].=20 </P> <P class=3D"">In 1997 Schulder et al., reported their experience with 13 = cases of=20 brain metastases treated with surgical resection and implantation of = permanent=20 low activity <SUP>125</SUP>I seeds. Included were individuals with = recurrent=20 tumors having already failed WBRT (8 patients), or who had initially = refused=20 WBRT with metastases too large for stereotactic radiosurgery (5 = patients). The=20 median calculated dose of <SUP>125</SUP>I was 82 Gy. This was a = good=20 performance status group of patients with a mean KPS of 84 and absent or = stable=20 systemic disease. Two patients died early; one who required evacuation = of a=20 hematoma in the resection cavity on the day after implantation then died = of=20 pulmonary embolus 2 weeks later and one with postoperative adult=20 respiratory distress syndrome. The mean survival of the remaining 11 was = 9 months and all had local control. One individual required surgery = for=20 symptomatic radiation necrosis and another for a combination of tumor = and=20 radiation necrosis. One patient developed a symptomatic cerebrospinal = fluid leak=20 requiring repair. This case series with no relative comparison to = another=20 therapy meets the criteria to provide class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR22">22</A></CITE>].=20 The high early mortality rate in this small study suggests that the use = of low=20 activity <SUP>125</SUP>I seeds in brain metastases should be relegated = to=20 properly conducted clinical trials. </P></DIV></DIV> <DIV class=3D""><A name=3DSec20></A> <DIV class=3DHeading3>Surgery and local chemotherapy with or without = whole brain=20 radiation therapy</DIV> <P class=3D"">Two single arm studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>]=20 met the criteria for inclusion of their data in this portion of the = guideline.=20 </P> <P class=3D"">In an assessment of an alternative modality to local = radiation=20 therapy, Ewend et al., described their experience with a prospectively = evaluated=20 group of 25 cases of newly diagnosed solitary metastatic tumors in good=20 performance status patients treated with surgical resection and Gliadel = wafer=20 implantation followed by WBRT (44 Gy in 22 fractions). The primary = goal was=20 to assess toxicity of this combination therapy, and the serious = toxicities=20 reported included seizures (<I>n</I> =3D 1), seizures and = respiratory=20 failure (<I>n</I> =3D 1), and the moderate toxicities included = nausea=20 (<I>n</I> =3D 2), constipation (<I>n</I> =3D 3), = right eye pain=20 (<I>n</I> =3D 1) and fever (<I>n</I> =3D 1). Median = follow-up=20 was 36.1 weeks and at that point median survival was 33 weeks. = No=20 local recurrences were reported but four patients developed distant = intracranial=20 recurrences and two patients had new metastases in the spinal canal. Of = the 16=20 deaths observed five were neurologic in nature. This data was obtained=20 prospectively, but without meaningful concurrent comparative data = rendering=20 class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P class=3D"">In a study of the feasibility of intracavitary=20 5-fluoro-2′-deoxyuridine (FdUrd) Nakagawa et al., report on six = brain metastases=20 patients in a series of 13 cases with malignant brain tumors. They point = out=20 that the goal of the use of this agent is to inhibit tumor DNA synthesis = by its=20 metabolite 5-fluoro-2=92deoxy-5=92-monophosphate. After claiming to show = intrathecal=20 administration of FdUrd was safe, the authors placed an Ommaya reservoir = in=20 =93small=94 fresh resection cavities and then administered 25=9630 daily = injections of=20 1=965 micrograms. They report no adverse events and three complete = responses (of=20 3, 10 and 32 weeks, respectively), one with stable disease and two = with=20 progressive disease. However, median follow-up time is not reported. = This data=20 was obtained prospectively, but with less than usual detail on = pretreatment and=20 post-treatment data and is without meaningful concurrent comparative = data=20 rendering it as class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR17">17</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec21></A> <DIV class=3DHeading3>Interstitial radiosurgery</DIV> <P class=3D"">Two case series [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>]=20 met the criteria for inclusion of their data in this portion of the = guideline.=20 To assess a device termed the Photon Radiosurgery System (PRS), Curry et = al.,=20 describe its use in the treatment of 60 patients with metastatic brain = tumors;=20 37 with solitary lesions and 23 with multiple lesions. They describe the = device=20 as a light weight x-ray generator that produces a point source of = low-energy=20 photons. The median age of the subjects was 58 years (range of=20 18=9683 years) and median KPS was 90. Prior treatment was variable. = PRS was=20 applied in cases not deemed suitable for resection due to location or = which were=20 undergoing diagnostic biopsy. Seven lesions were larger than 3 cm = in=20 diameter and only one in the entire series was in the cerebellum. The = device was=20 introduced utilizing a stereotactic frame. The median dose was = 16 Gy to a=20 point 2 mm beyond the enhancing tumor margin. The authors chose to = report=20 local control as their primary outcome and did so after a median = follow-up of=20 6 months (with a range of 5 days to 31 months). = Seventy-two=20 lesions were treated. Local control was present in 81%. Median survival = was=20 8 months from treatment. Of the 46 cases that went onto death, 30% = were=20 neurologic in nature. Four patients experienced perioperative seizures = that were=20 easily controlled with anticonvulsant medications and were not = recurrent, three=20 experienced transient neurological deficits thought to be associated = with the=20 biopsy or due to treatment induced cerebral edema, and two experienced = biopsy=20 related hemorrhages. Three patients experienced symptomatic radiation = necrosis=20 requiring surgical debridement and corticosteroid therapy. This case = series with=20 no concurrent comparison to another therapy meets the criteria to = provide class=20 III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR23">23</A></CITE>].=20 </P> <P class=3D"">In an attempt to avoid WBRT as an initial treatment in = patients with=20 metastatic brain tumors Nakamura et al., reported a case series of 43 = patients=20 whose solitary lesions were treated with intraoperative radiosurgery = with=20 high-energy electron beams generated by a 20 MeV betatron. Therapy = was=20 delivered over 5=9610 min to a dose of 18=9625 Gy with = 8=9616 MeV to=20 one cm beyond the margins of a fresh resection bed. They also mention = that=20 progression was treated with additional radiation but this was not = standardized.=20 One year survival was 53%. Median follow-up was not reported, but seven = patients=20 developed local recurrence and seven patients developed brain = recurrences=20 distant from the primary site. Two individuals developed radiation = necrosis at=20 the treatment site but were managed without surgery. The authors discuss = other=20 patients treated for brain metastases at their institution utilizing = various=20 combinations of therapy but fail to provide systematic pretreatment and=20 follow-up data so as to make a meaningful comparison. Thus the data from = this=20 paper qualifies as class III evidence [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR24">24</A></CITE>].=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec22></A> <HR> <DIV class=3Dheading2>Interstitial therapy summary</DIV> <P class=3D"">Interstitial therapies are appealing as their intent is to = maximize=20 treatment of the metastatic pathology and preserve surrounding normal = tissue.=20 The data presented here does not allow creation of level 1 or level 2=20 recommendations. The interstitial use of radiation and cytotoxic = chemotherapy=20 appears feasible but not without toxicity. Furtherance of these = modalities will=20 be dependent on truly prospective and comparative study designs in order = to=20 obtain meaningful information. </P> <DIV class=3D""><A name=3DSec23></A> <DIV class=3DHeading3>New chemotherapeutic agents</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided 31 unique studies that = met the=20 criteria for support of guidelines recommendations regarding the use of=20 chemotherapeutic agents in the management of brain metastases = (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab4">4</A>).=20 The use of temozolomide was reported in 25 studies of which two were = evidence=20 class I studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>],=20 two were evidence class II studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>],=20 and 21 were evidence class III studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>].=20 In most of the studies included in this discussion the primary tumor = treated was=20 melanoma, though other primary tumor sites were addressed.<A = name=3DTab4></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 4 </SPAN>Summary = of primary=20 chemotherapy 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/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"">Tumor response</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"">TMZ</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Abrey [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">6.62 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete response 0/41 (0%)</P> <P class=3D"">Partial response 2/41 (4.9%)</P> <P class=3D"">Stable disease 15/41 (36.6%)</P> <P class=3D"">Progressive disease 17/41 (41.5%)</P> <P class=3D"">Not assessed 7/41 (17.1%)</P></TD> <TD align=3Dleft> <P class=3D"">Overall in brain: 1.97 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Addeo [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + TMZ (<I>n</I> =3D 59) = </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">13 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 44% (CR: 5/59; PR 21/59)</P> <P class=3D"">Stable Disease: 19/59 (32.3%)</P> <P class=3D"">Progressive Disease: 14/59 (23.7%)</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression: = 9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Agarwala [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 151) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">3.2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 6% (CR 1/151; PR 8/151)</P> <P class=3D"">Stable disease: 40/151 (26%)</P> <P class=3D"">Progressive disease: 73/151 (48%)</P> <P class=3D"">Not evaluable: 29/151 (19%)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: Pts with prior = chemo:=20 1 month</P> <P class=3D"">Chemo na=EFve pts: 1.2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Antonadou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">Randomized phase II trial</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 23) </P> <P class=3D"">G2: WBRT + TMZ (<I>n</I> =3D 25) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from lung, breast or unknown primary</P></TD> <TD align=3Dleft> <P class=3D"">G1: 7.0 months</P> <P class=3D"">G2: 8.6 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (Of evaluable pts)</P> <P class=3D"">G1: OR 67% (CR 7/21, PR 7/21)</P> <P class=3D"">G2: OR 96% (CR 9/24, PR 14/24) = (<I>p</I> =3D 0.017)=20 </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bafaloukos [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR39">39</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Sub-group analysis of two Phase II studies</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ-based chemotherapy (<I>n</I> =3D 25) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">4.7 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 24% (CR 0/25;</P> <P class=3D"">PR 6/25)</P> <P class=3D"">Stable disease 5/25</P> <P class=3D"">Progressive disease 13/25</P> <P class=3D"">Not evaluable 1/25</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression:</P> <P class=3D"">2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Boogerd [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Sub-group analysis of three prospective studies</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ =B1 immunotherapy = (<I>n</I> =3D 52 with=20 BM) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">5.6 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Only reported for sub-group of 13/52 pts who had a = response to=20 TMZ at extra-cranial sites:</P> <P class=3D"">Complete response 3/13</P> <P class=3D"">Partial response 2/13</P> <P class=3D"">Stable disease 6/13</P></TD> <TD align=3Dleft> <P class=3D"">NR overall</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Caraglia [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + pegylated liposomal doxorubicin=20 (<I>n</I> =3D 19) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">10 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR36.8% (CR 3/19; PR 4/19)</P> <P class=3D"">Stable Disease 8/19 (42.1%)</P> <P class=3D"">Progressive Disease 4/19 (21%)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 5.5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + cisplatin = (<I>n</I> =3D 32) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">5.5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response both in brain +</P> <P class=3D"">Extra-cranial sites:</P> <P class=3D"">Complete response 1/32</P> <P class=3D"">Partial response 8/32</P> <P class=3D"">Partial response in brain only 1/32</P> <P class=3D"">Stable disease 5/32</P> <P class=3D"">Progressive disease 6/32</P> <P class=3D"">Not evaluable 11/32</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression for all pts:=20 2.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Christodoulou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>]=20 (2001) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 28) </P></TD> <TD align=3Dleft> <P class=3D"">BM</P></TD> <TD align=3Dleft> <P class=3D"">4.5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 4% (CR 0/27; PR 1/27)</P> <P class=3D"">Stable disease 4/27</P> <P class=3D"">Progressive disease or death: 14/27</P> <P class=3D"">Not assessable: 3/27</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression: = 3 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Conill [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>]=20 (2006) </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 Gy/5 fractions + TMZ based = chemotherapy=20 (<I>n</I> =3D 11) </P> <P class=3D"">G2: 30 Gy/10 fractions + TMZ based = chemotherapy=20 (<I>n</I> =3D 10) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.0 months G2: 4.0 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Data not reported by group;</P> <P class=3D"">No statistically significant difference between = groups=20 (<I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Cortot [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + cisplatin followed by WBRT=20 (<I>n</I> =3D 50; 68% had WBRT) </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response (CR 2%<B>;</B> PR 10%) </P> <P class=3D"">Stable disease: 42%</P> <P class=3D"">Progressive disease: 40%</P> <P class=3D"">Not assessable: 6%</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression: = 2.3 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Giorgio [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 30) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">6 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete response 2/30 (6.7%)</P> <P class=3D"">Partial response 1/30 (3.3%)</P> <P class=3D"">Stable disease 3/30 (10%)</P> <P class=3D"">Progressive disease 24/30 (80%)</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression of brain metastases in = all pts:=20 3.6 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hofmann [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR45">45</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ =B1 SRS or WBRT = (<I>n</I> =3D 35) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">8 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain + extra-cranial = sites:</P> <P class=3D"">(Of 34 evaluable pts)</P> <P class=3D"">Complete remission: 1/34 (3%)</P> <P class=3D"">Partial remission: 2/34 (6%)</P> <P class=3D"">Stable disease: 9/34 (26.4%)</P> <P class=3D"">Mixed response (PR or stable disease in brain, but=20 extra-cranial disease progression): 5/34 (14.7%)</P> <P class=3D"">Progressive disease: 17/34 (50%)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: = 5 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hwu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + thalidomide = (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete response 2/26</P> <P class=3D"">Partial response 1/26</P> <P class=3D"">Minor response/stable: 7/26</P> <P class=3D"">Progressive disease: 4/26</P> <P class=3D"">Unknown 1/26</P> <P class=3D"">Not assessable 11/26</P></TD> <TD align=3Dleft> <P class=3D"">Median duration of response or stable disease in = brain:=20 4 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Iwamoto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>]=20 (2008) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 38) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/refractory BM</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 5% (CR 1/38; minor response = 1/38)</P> <P class=3D"">Stable disease 5/38</P> <P class=3D"">Progressive disease 29/38</P> <P class=3D"">Not evaluable 2/38</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: = 1.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Janinis [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR48">48</A></CITE>]=20 (2000) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 11) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 8 pts evaluable)</P> <P class=3D"">Partial response 1/8</P> <P class=3D"">Minor response 3/8</P> <P class=3D"">Stable disease 1/8</P> <P class=3D"">Progressive disease: 3/8</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Kouvaris [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + TMZ (<I>n</I> =3D 33) = </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">12 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">After 3 cycles of TMZ:</P> <P class=3D"">OR 54.5% (CR 7/33;</P> <P class=3D"">PR 11/33)</P> <P class=3D"">After 6 cycles of TMZ:</P> <P class=3D"">OR 57.6% (CR 8/33; PR 11/33)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 11 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Krown [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + thalidomide = (<I>n</I> =3D 16) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">23.9 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 0/16 (ITT analysis)</P></TD> <TD align=3Dleft> <P class=3D"">Progression-free survival: = 7.3 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Larkin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I/II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + lomustine = (<I>n</I> =3D 26) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (In phase II; = <I>n</I> =3D 20) </P> <P class=3D"">Response rate 0/20</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Margolin [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>]=20 (2002) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + WBRT (<I>n</I> =3D 31) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">6 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 9.7% (CR 1/31; PR 2/31)</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 2 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Omuro [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + vinorelbine = (<I>n</I> =3D 21) </P></TD> <TD align=3Dleft> <P class=3D"">Recurrent/progressive BM</P></TD> <TD align=3Dleft> <P class=3D"">17 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 18 evaluable pts)</P> <P class=3D"">Partial response 1/18</P> <P class=3D"">Minor response 1/18</P> <P class=3D"">Stable disease 6/18</P> <P class=3D"">Progressive disease 10/18</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Panagiotou [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>]=20 (2005) </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 5) </P> <P class=3D"">G2: TMZ (initial tx) + WBRT (after = progression)=20 (<I>n</I> =3D 17) </P> <P class=3D"">G3: WBRT (<I>n</I> =3D 28) </P> <P class=3D"">G4: Supportive care (<I>n</I> =3D 14) = </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 12 months</P> <P class=3D"">G2: 5 months</P> <P class=3D"">G3: 3 months</P> <P class=3D"">G4: 2 months</P> <P class=3D"">(Survival curves G2 vs. G3 log-rank;=20 <I>p</I> =3D 0.0267) </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""> Rivera [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase I study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ + capecitabine = (<I>n</I> =3D 24) </P></TD> <TD align=3Dleft> <P class=3D"">BM from breast cancer</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 22 evaluable pts)</P> <P class=3D"">OR 18% (CR1/22; PR 3/22)</P> <P class=3D"">Minor response or stable disease 11/22</P> <P class=3D"">Progressive disease 7/22</P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression of brain metastases:=20 12 weeks</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Schadendorf [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>]=20 (2006) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">TMZ (<I>n</I> =3D 45) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">4.1 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 4.4% (CR 0/45; PR 2/45)</P> <P class=3D"">Stable disease 5/45</P> <P class=3D"">Progressive disease 33/45</P> <P class=3D"">Not evaluable 5/45</P></TD> <TD align=3Dleft> <P class=3D"">NR overall</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Verger [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>]=20 (2003) </P></TD> <TD align=3Dleft> <P class=3D"">Randomized phase II trial</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 41) </P> <P class=3D"">G2: WBRT + TMZ (<I>n</I> =3D 41) = </P></TD> <TD align=3Dleft> <P class=3D"">Newly diagnosed BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 3.1 months</P> <P class=3D"">G2: 4.5 months</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response in brain at 30 days: (by ITT)</P> <P class=3D"">G1: OR 32% (CR 2/41, PR 11/41)</P> <P class=3D"">G2: OR 32% (CR 2/41, PR 11/41) = (<I>p</I> =3D NS) </P> <P class=3D"">Response in brain at 90 days:</P> <P class=3D"">G1: OR 2/41 (CR 0/41, PR 2/41)</P> <P class=3D"">G2: OR 7/41 (CR 1/41, PR 6/41) = (<I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median: Not reported</P> <P class=3D"">% BM progression-free at 90 days:</P> <P class=3D"">G1: 54%</P> <P class=3D"">G2: 72% (<I>p</I> =3D 0.03) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Fotemustine</P></TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Br=F6cker [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">WBRT + fotemustine = (<I>n</I> =3D 13) </P></TD> <TD align=3Dleft> <P class=3D"">Progressive multiple BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">Overall: Not reported</P> <P class=3D"">Pts with partial response/stable disease: = 6 months</P> <P class=3D"">Other pts: 2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (12 evaluable pts)</P> <P class=3D"">Complete response: 0/13</P> <P class=3D"">Partial response 4/13</P> <P class=3D"">Stable disease 3/13</P> <P class=3D"">Progressive disease 6/13</P> <P class=3D"">Not assessable: 1/13</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Chang [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>]=20 (1994) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Dacarbazine + fotemustine = (<I>n</I> =3D 34)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">4.5 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">OR 12% (CR 2/34; PR 2/34)</P> <P class=3D"">Stable disease 9/34</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Cotto [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR62">62</A></CITE>]=20 (1996) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Fotemustine + Cisplatin = (<I>n</I> =3D 31)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">16 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of 25 evaluable pts)</P> <P class=3D"">OR 16% (CR 2/25; PR 2/25)</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Jacquilat [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>]=20 (1990) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Fotemustine (<I>n</I> =3D 39) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">26 weeks</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Objective response 28% (CR 2/39; PR 9/39)</P> <P class=3D"">Stable disease 9/39</P> <P class=3D"">Progressive disease 19/39</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mornex [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>]=20 (2003) </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: Fotemustine (<I>n</I> =3D 39) </P> <P class=3D"">G2: Fotemustine + WBRT = (<I>n</I> =3D 37)=20 </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 86 days</P> <P class=3D"">G2: 105 days</P> <P class=3D"">(Survival curves: log-rank; = <I>p</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain at day 50 (by ITT)</P> <P class=3D"">G1: OR 5.1% (CR 0/39, PR 2/39)</P> <P class=3D"">G2: OR 8.1% (CR 0/37, PR 3/37) = (<I>p</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression in brain:</P> <P class=3D"">G1: 49 days</P> <P class=3D"">G2: 80 days</P> <P class=3D"">(BM progression-free curves; Wilcoxon:=20 <I>p</I> =3D 0.03; log-rank: = <I>p</I> =3D 0.069)=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ulrich [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>]=20 (1999) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P = class=3D"">WBRT + fotemustine =B1 dacarbazine=20 (<I>n</I> =3D 12) </P></TD> <TD align=3Dleft> <P class=3D"">BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">Mean survival of responders:</P> <P class=3D"">8.2 months</P></TD> <TD align=3Dleft> <P class=3D"">Response in brain:</P> <P class=3D"">Complete remission 4/12</P> <P class=3D"">Partial remission 2/12</P></TD> <TD align=3Dleft> <P class=3D"">Median: NR</P> <P class=3D"">Mean progression free survival:=20 6.1 months</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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>LR</I> Local recurrence at original site in = brain,=20 <I>MGd</I> Motexafin-gadolinium, <I>NR</I> Not reported, <I>NS</I> Not=20 significant, <I>NSCLC</I> Non-small cell lung cancer, <I>OR</I> = Objective=20 response, <I>PR</I> Partial response, <I>Pts</I> Patients, <I>RCT</I> = Randomized=20 control trial, <I>SRS</I> Stereotactic radiosurgery, <I>TMZ</I> = Temozolomide,=20 <I>WBRT</I> Whole-brain radiation therapy=20 </DIV></DIV></DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec24></A> <HR> <DIV class=3Dheading2>Temozolomide</DIV> <DIV class=3D""><A name=3DSec25></A> <DIV class=3DHeading3>Prospective randomized phase II studies</DIV> <P class=3D"">In the first of the class I studies Antonadou et al., = carried out a=20 randomized phase II study of 48 individuals with lung cancer, breast = cancer or=20 unknown primaries. Group 1 received WBRT to 40 Gy in 2 Gy = fractions=20 and group 2 received oral temozolomide (TMZ, 75 mg/m=B2/d) = concurrent with=20 WBRT 40 Gy in 2 Gy fractions and then continued TMZ therapy=20 (200 mg/m=B2/d) for 5 days every 28 days for an = additional maximum=20 of 6 cycles after WBRT was completed. The clinical and pathologic=20 characteristics of the groups were well balanced. The response rate in = group 2=20 was 96% as opposed to 67% in group 1, a significant difference=20 (<I>p</I> =3D 0.017). This better response rate was at the = cost of=20 significantly more nausea and vomiting in group 2. There was no grade 3 = or grade=20 4 myelosuppression. However, median survival was 7.0 months in = group 1 and=20 8.6 months in group 2, a difference that did not reach significance = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR32">32</A></CITE>].=20 </P> <P class=3D"">The second class I study by Verger et al., was also a = randomized=20 phase II study of patients with newly diagnosed brain metastases from = any=20 source. Group 1 received 30 Gy WBRT in 10 fractions and group 2 = received=20 30 Gy WBRT in 10 fractions with concurrent TMZ during radiation=20 (75 mg/m=B2/day), followed by two cycles of TMZ = (200 mg/m=B2/day) for=20 5 days of a 28 day cycle. The clinical and pathology = characteristics=20 of each group were not significantly different. Progression free = survival from=20 brain metastases 90 days after randomization was 72% in group 2 and = 54% in=20 group 1, a statistically significant advantage = (<I>p</I> =3D 0.03). Also=20 group 1 had a greater percentage dying a neurologic death (69%) than in = group 2=20 (41%), again a significant difference (<I>p</I> =3D 0.029). = Despite=20 these differences, there was no advantage in median survival of group 2 = over=20 group 1 (4.5 months and 3.1 months, respectively) and no = difference in=20 response rates. Additionally, clinically significant toxicity was only = observed=20 in group 2 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR33">33</A></CITE>].=20 In summary, neither of these well done randomized phase II studies = demonstrated=20 a meaningful benefit to survival by adding TMZ. </P></DIV> <DIV class=3D""><A name=3DSec26></A> <DIV class=3DHeading3>Retrospective cohort analyses</DIV> <P class=3D"">Both of the class II studies regarding the use of TMZ were = retrospective cohort analyses [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>].=20 In the first study Panagioutou et al., described their experience with = 64=20 patients with melanoma brain metastases. Four groups were evaluated = according to=20 treatment. Group A was treated with surgery followed by WBRT, Group B = was=20 treated with TMZ at initial diagnosis and with WBRT at progression, = Group C was=20 treated with WBRT alone, and Group D received supportive care alone. The = median=20 survivals were 12, 5, 3, and 2 months, respectively. The survival = in the=20 TMZ at initial diagnosis and WBRT at progression group was significantly = greater=20 than the WBRT alone group (<I>p</I> =3D 0.0267 by log rank). = Patient=20 characteristics influenced treatment selection. Age and intracranial = extent of=20 disease were not well balanced and performance status was not assessed = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR35">35</A></CITE>].=20 In a study that mainly looked at differing radiation doses Conill et = al.,=20 reviewed a group of 21 individuals with melanoma brain metastases who = were=20 treated with WBRT (20 Gy in 5 fractions) and TMZ-based chemotherapy = (<I>n</I> =3D 11), or WBRT (30 Gy in 10 fractions) and = TMZ-based=20 chemotherapy (<I>n</I> =3D 11). The actual chemotherapy = regimens varied=20 substantially, with some patients receiving other agents in addition. = The extent=20 of disease and performance status was reasonably well balanced between = the two=20 groups and the median survival in both groups was 4 months = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR34">34</A></CITE>].=20 Again, in these class II studies, one cannot conclude TMZ imparts a = survival=20 advantage. </P></DIV> <DIV class=3D""><A name=3DSec27></A> <DIV class=3DHeading3>Prospective phase II studies</DIV> <P class=3D"">Among the 21 remaining studies qualifying for inclusion in = this=20 guideline all were class III data. Five were prospective phase II = studies in=20 which TMZ was utilized alone [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>].=20 Agarwala et al., reported their prospective experience with 151 patients = with=20 newly diagnosed brain melanoma metastases treated with TMZ=20 (150 mg/m<SUP>2</SUP>/day for patients with prior chemotherapy, or=20 200 mg/m<SUP>2</SUP>/day for chemotherapy na=EFve patients, for = 5 days,=20 every 28 days for 1 year or until disease progression or = unacceptable=20 toxicity). Median survival was 3.2 months and objective response = (complete=20 response or partial response) was noted in 6% [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR38">38</A></CITE>].=20 Schadendorf et al., treated 45 individuals with known melanoma who had = developed=20 new brain metastases with TMZ (125 mg/m<SUP>2</SUP>/day in patients = who had=20 received prior chemotherapy or 150 mg/m=B2/day in previously = untreated=20 patients, on days 1=967 and days 15=9621 very 28 days). Median = survival was=20 4.1 months with two partial responses and five patients with stable = disease=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR55">55</A></CITE>].=20 In another study of newly diagnosed brain metastases Christadoulou et = al. looked=20 at individuals with a wide variety of primaries that had already = received=20 substantial systemic therapy for their cancer. All = (<I>n</I> =3D 28)=20 received TMZ (150 mg/m<SUP>2</SUP>/day for 5 days every = 4 weeks=20 until progression or unacceptable toxicity). Median survival in the = entire group=20 was 4.5 months with only one partial response [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR43">43</A></CITE>].=20 Abrey et al., looked at 41 individuals with recurrent or progressive = brain=20 metastases from various primaries (22 were NSCLC) treated with TMZ = (patients who=20 had received chemotherapy before received TMZ = 150 mg/m<SUP>2</SUP>/day for=20 5 days, and chemotherapy na=EFve patients received=20 200 mg/m<SUP>2</SUP>/day for 5 days with treatment cycles = repeated=20 every 28 days). Two partial responses were observed. Overall median = survival was 6.62 months in all participants [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR36">36</A></CITE>].=20 Giorgio et al., looked at a series of patients with NSCLC whose brain = metastases=20 had progressed after WBRT and one regimen of chemotherapy=20 (<I>n</I> =3D 30). Two complete responses and one partial = response were=20 reported. Median survival was six months [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR44">44</A></CITE>].=20 Though individuals with NSCLC seemed to survive slightly longer than = those with=20 melanoma in these five studies no meaningful comparison or statistical=20 assessment can support such a conclusion. </P> <P class=3D"">In a sixth prospective single armed study Janinis reported = on 11=20 patients with melanoma brain metastases who had not received = radiotherapy, who=20 were treated with TMZ (200 mg/m<SUP>2</SUP>/day for 5 days = every=20 28 days for chemotherapy na=EFve patients and = 150 mg/m<SUP>2</SUP>/day=20 for 5 days every 28 days for patients treated with prior=20 chemotherapy). Survivals ranged from 10 days to over 13 months = but no=20 median was reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR48">48</A></CITE>].=20 Though this publication met the criteria for being included in this = guideline,=20 the small size and lack of comparative data does not yield information = that=20 provides direction for therapy in brain metastases. </P> <P class=3D"">In three of the prospective phase II studies yielding = class III=20 data, TMZ was used with WBRT [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>].=20 Margolin et al., assessed 31 individuals with newly diagnosed melanoma = brain=20 metastases treated with TMZ at 75 mg/m<SUP>2</SUP>/day started on = day 1 and=20 continued daily for 6 weeks and then repeated every 10 weeks = along=20 WBRT to a total dose of 30 Gy in 10 fractions on days 1=965 and = 8=9612. Though=20 all cases had a WHO performance status of 0 or 1 the median survival was = just=20 6 months and only one complete response and two partial responses = were=20 observed [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>].=20 In a more recent study Addeo et al., describe the use of WBRT to a dose = of=20 30 Gy in 10 fractions with concomitant TMZ = (75 mg/m<SUP>2</SUP>/day)=20 for 10 days, and subsequent TMZ (150 mg/m<SUP>2</SUP>/day = every=20 28 days) for up to 6 cycles in 59 patients with newly diagnosed = brain=20 metastases from various sources. Median survival was 13 months with = 5=20 complete responses and 21 partial responses being noted to yield a 44% = objective=20 response rate. In another study looking at brain metastases from a = variety of=20 primary sites, Kouvaris et al., reported the use of combined therapy = with WBRT=20 to a total dose of 36 Gy in 12 fractions given in 16 days = along with=20 TMZ 60 mg/m=B2/day (days 1=9616) followed by 6 cycles of TMZ=20 (200 mg/m=B2/day for 5 consecutive days every 28 days). Median = survival=20 was 12 months with seven complete responses and 11 partial = responses being=20 noted for an overall objective response rate of 54.5% with the objective = response rate in patients with lung cancer being 78.6%. Interestingly, = 45.5% of=20 individuals in this study experienced hepatotoxicity, attributed to the = use of=20 anticonvulsants in these patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>].=20 The improved survival seen here and in the Addeo et al., study as = opposed to the=20 Margolin study may be more related to the underlying primary tumor = histologies=20 than to the advantage provided by the alteration in the TMZ = administration=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR37">37</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR49">49</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR52">52</A></CITE>].=20 </P> <P class=3D"">One other prospective phase II study of WBRT and TMZ also = included=20 the use of cisplatin but with both cytotoxic agents administered before=20 radiation [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>].=20 Cortot et al., studied 50 patients with NSCLC brain metastases treated = with TMZ=20 (200 mg/m<SUP>2</SUP>/day for 5 days every 28 days) and = cisplatin=20 (75 mg/m<SUP>2</SUP>) on day 1 of each cycle, for up to 6 cycles = followed=20 by WBRT to a total of 30 Gy in 10 fractions. WBRT was performed at = time of=20 progressive disease (at any time) or in patients with stable disease = after 4=20 cycles. Median survival was 5 months and one complete response and = five=20 partial responses were noted [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR56">56</A></CITE>].=20 Though methodological differences prevent meaningful comparisons between = this=20 and the studies of Addeo, Kouvaris and Margolin, the addition of = cisplatin did=20 not appear to provide an overt survival or response benefit. </P> <P class=3D"">In the six remaining prospective phase II studies TMZ was = used in=20 combination with a variety of other systemic agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>].=20 These included thalidomide, cisplatin, vinorelbine, pegylated liposomal=20 doxorubicin, and lomustine utilized for a variety of tumor types and at = either=20 new diagnosis or at recurrence. Median survival was as short as = 2 months in=20 the report by Larkin et al., who utilized TMZ at = 150 mg/m<SUP>2</SUP> on=20 days 1 through 5 every 28 days and lomustine = 60 mg/m<SUP>2</SUP> on=20 cycle day 5 every 56 days in patients with newly diagnosed melanoma = brain=20 metastases[<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>].=20 The longest median survival in this group of six studies was = 10 months in=20 the report of Caraglia et al., who used TMZ at 200 mg/m=B2 on days = 1 through=20 5 and pegylated liposomal doxorubicin at 35 mg/m=B2 on day 1 of = every=20 28 day cycle for up to 8 cycles in individuals with progressive = metastases=20 failing initial therapy. In this study, only one individual had a = melanoma=20 primary[<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>].=20 Here again, the underlying characteristics of the different studies are = too=20 disparate to allow meaningful comparisons to establish the superiority = or=20 inferiority of one regimen to another. They do, however, reflect the = known poor=20 prognosis of patients with melanoma once intracranial metastases develop = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR42">42</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR46">46</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR47">47</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR50">50</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR51">51</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec28></A> <DIV class=3DHeading3>Prospective phase I studies</DIV> <P class=3D"">There were two prospective phase I studies utilizing TMZ = and other=20 management in the series of papers meeting this guideline=92s criteria = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>].=20 In the first Omuro et al., describe the use of 28 day cycles of TMZ = at=20 150 mg/m<SUP>2</SUP> on days 1 through 7 and 15 through 21 and = vinorelbine=20 on days 1 and 8 using escalating doses with a starting dose of=20 15 mg/m<SUP>2</SUP> with increments of 5 mg/m<SUP>2</SUP> for = each=20 cohort of 3=966 patients until 30 mg/m<SUP>2</SUP>. The maximum = tolerated=20 dose was declared at 30 mg/m<SUP>2</SUP> and, though not a primary = goal of=20 the study, it was noted median survival of the patients treated was=20 17 weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR53">53</A></CITE>].=20 In the other study Rivera et al., looked for a maximum tolerated dose of = TMZ and=20 capecitabine. Four sequential cohorts were treated at different dosing = levels on=20 days 1 through 5 and days 8 through 12 with cycles repeated every = 21 days.=20 Respective dosing ranges of capecitabine and TMZ were=20 1600=962000 mg/m<SUP>2</SUP> and 50=96150 mg/m<SUP>2</SUP>. = Maximum=20 tolerated dose was not reached. No median survival was reported but, = among the=20 24 cases enrolled one complete response and two partial responses were = noted=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR54">54</A></CITE>].=20 Though these two studies meet criteria for inclusion in these = guidelines, they=20 add little to development of a consensus on how TMZ, alone or in = combination=20 with other agents would play a role in the therapy of brain metastases.=20 </P></DIV> <DIV class=3D""><A name=3DSec29></A> <DIV class=3DHeading3>Combined subgroup analyses from multiple = publications</DIV> <P class=3D"">Two of the studies involving TMZ therapy of brain = metastases were=20 subgroup analyses combined from prior prospective studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR39">39</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>].=20 Bafaloukos et al., combined the data from two publications of the = Hellenic=20 Cooperative Oncology Group evaluating patients with melanoma brain = metastases.=20 Twenty-five individuals treated with TMZ at a dose of=20 150=96200 mg/m<SUP>2</SUP>/day on days 1 through 5 every = 4 weeks alone=20 or with either docetaxel (80 mg/m<SUP>2</SUP> on day 1) or = cisplatin=20 (75 mg/m<SUP>2</SUP> on day 1). Median survival combining all = patients was=20 4.7 months. Six partial responses were observed distributed between = the=20 three groups. No obvious superiority of one regimen was discerned over = another=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR39">39</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR57">57</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR58">58</A></CITE>].=20 In the publication by Boogerd et al., data was combined from three = different=20 studies. Fifty-two patients with brain metastases were evaluable who = were=20 treated with TMZ at doses from 150 to 250 mg/m<SUP>2</SUP>/day for=20 5 days every 4 weeks followed by immunotherapy=20 granulocyte=96macrophage-colony stimulating factor (2.5 μg/kg), = interleukin-2 (4=20 MIU/m<SUP>2</SUP>), and IFNα (5 MIU fixed dose) for 12 days=20 (<I>n</I> =3D 23) or who were treated with TMZ alone=20 (200 mg/m<SUP>2</SUP>/day for 5 days every 4 weeks)=20 (<I>n</I> =3D 29). Out of the 52 patients the authors focused = on the 13=20 with evidence of systemic response noting that their neurologic = stabilization or=20 responses seemed to be more meaningful. The median survival for all 52 = was=20 5.6 months. The authors were unable to conclude the superiority of = one=20 regimen over the other [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR40">40</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec30></A> <DIV class=3DHeading3>Retrospective case series</DIV> <P class=3D"">The last class III study qualifying for inclusion in this = guideline=20 was a simple retrospective case series of 35 patients, all treated with = TMZ=20 (200 mg/m<SUP>2</SUP> for 5 days every 28 days) with 12 = receiving=20 stereotactic radiosurgery and with ten receiving WBRT. Median survival = was=20 8 months with one complete response and two partial responses = observed; the=20 longest duration being 16 months. The authors concluded the results = were=20 =93favorable=94 but appropriately did not attempt to compare the groups = for=20 superiority [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR45">45</A></CITE>].=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec31></A> <HR> <DIV class=3Dheading2>Fotemustine</DIV> <P class=3D"">The use of fotemustine was addressed in six studies, one = of which=20 was evidence class I [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>]=20 and five of which were evidence class III [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>].=20 Five of the six included only brain metastases from melanoma [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>].=20 </P> <DIV class=3D""><A name=3DSec32></A> <DIV class=3DHeading3>Randomized controlled study</DIV> <P class=3D"">The study by Mornex et al., was a randomized controlled = study of 76=20 individuals with brain metastases from melanoma yielding class I data. = Group 1=20 received fotemustine intravenously at a dose of = 100 mg/m<SUP>2</SUP> on=20 days 1, 8, and 15 followed by a 5 week rest period followed by a = single=20 dose every 3 weeks thereafter. Group 2 received the same dosage = regimen of=20 fotemustine with the addition of WBRT at a dose 37.5 Gy delivered = in 15=20 fractions over 3 consecutive weeks. Gender, age, extent of systemic = disease, and=20 number of intracranial metastases were balanced. The performance status = of group=20 2 was significantly better than in group 1 = (<I>p</I> =3D 0.019).=20 Utilizing intent to treat analysis there was no difference in survival, = response=20 rate (complete responses combined with partial responses) or tumor = control=20 (defined as complete responses combined with partial responses and = stable=20 disease) between the two groups. Median time to cerebral progression was = longer=20 in the patients treated with both being 49 days in group 1 and = 80 days=20 in group 2 (<I>p</I> =3D 0.069) [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR59">59</A></CITE>].=20 No newer studies of fotemustine in this patient group have met criteria = for=20 inclusion in this guideline. </P></DIV> <DIV class=3D""><A name=3DSec33></A> <DIV class=3DHeading3>Prospective single armed phase II studies</DIV> <P class=3D"">In the class III studies an array of uses of this therapy = and=20 subsequent outcomes can be found. In one study using fotemustine alone = for brain=20 metastases from melanoma Jacquilat et al., described 39 individuals who = had a=20 median survival of 26 weeks from initiation of therapy. There were = two=20 complete responses and nine partial responses with the median duration = of=20 response being 11 weeks. The promising nature of this study, = published=20 prior to the other studies meeting criteria for inclusion in this = guideline,=20 likely spurred the additional investigations that have been noted = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>].=20 Brocker et al., reported the use of WBRT and fotemustine in 13 patients = with=20 melanoma brain metastases not amenable to surgery or stereotactic = radiotherapy,=20 with seven achieving partial response or stable disease. Among those = seven=20 median survival was 6 months and survival in the rest was = 2 months=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR60">60</A></CITE>].=20 In a somewhat larger study Chang et al., combined fotemustine with = dacarbazine=20 in a group of 34 patients with brain metastases from melanoma whose = median=20 survival was 4.5 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>].=20 Cotto et al., reported a series of 31 individuals with brain metastases = from=20 NSCLC treated with fotemustine plus cisplatin. Twenty-five cases were = evaluable=20 for response with two achieving complete response and two achieving = partial=20 response. Median survival was reported as 16 weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR62">62</A></CITE>].=20 Hematologic toxicity in both the Chang and the Cotto studies was in = excess of=20 that seen with the use of fotemustine alone as noted by Jacquilat = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR61">61</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR63">63</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec34></A> <DIV class=3DHeading3>Case series</DIV> <P class=3D"">Ulrich et al., reported their case series of 12 patients = with brain=20 metastases from melanoma who were treated with induction therapy of = fotemustine=20 at 100 mg/m=B2 once a week with simultaneous WBRT to a total dose = ranging=20 from 32 to 58 Gy followed by maintenance treatment with = 100 mg/m=B2=20 fotemustine every 4 weeks thereafter. Two of the 12 individuals = received=20 dacarbazine 200 mg/m<SUP>2</SUP> on days 3 and 5 of the first = 2 weeks.=20 Six individuals had complete or partial intracranial remission and = amongst those=20 the mean survival was 8.2 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR64">64</A></CITE>].=20 Grade 3 or 4 thrombocytopenia was seen in four cases and grade 3 or 4 = leukopenia=20 was seen in four cases. The variation in radiation doses and systemic=20 chemotherapy (16% of cases receiving dacarbazine) results in the data = from this=20 publication being classified as class III. </P></DIV></DIV> <DIV class=3D""><A name=3DSec35></A> <HR> <DIV class=3Dheading2>Chemotherapy agent summary</DIV> <P class=3D"">Although class I, II and III data could be discerned from = the=20 literature regarding the use of TMZ and fotemustine in the treatment of = brain=20 metastases, meaningful survival benefit could only be demonstrated when=20 subjected to rigorous analysis in patients with melanoma metastases when = added=20 to WBRT. There were numerous reports of individuals who benefited in one = form or=20 another from the use of these agents and it cannot be concluded that = there might=20 not be a specific circumstance where TMZ or fotemustine are of value in = the=20 therapy of brain metastases. To improve this situation, investigations = of these=20 and other systemically administered agents is clearly warranted. </P> <DIV class=3D""><A name=3DSec36></A> <DIV class=3DHeading3>Molecular targeted agents</DIV> <DIV class=3DPara> <DIV class=3D"">Review of the literature provided six unique studies = that met the=20 criteria for support of guidelines recommendations regarding the use of=20 molecular targeted agents in the management of brain metastases = (Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab5">5</A>).<A=20 name=3DTab5></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 5 </SPAN>Summary = of molecular=20 targeted agents </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">First author(year)</P></TH> <TH align=3Dleft> <P class=3D"">Study design/evidence class</P></TH> <TH align=3Dleft> <P class=3D"">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"">Tumor response</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"">Gefitinib</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Ceresoli [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR71">71</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 41) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">5 months</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 10%</P> <P class=3D"">(CR 0/41; PR 4/41)</P> <P class=3D"">Stable disease: 7/41</P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival: = 3 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Chiu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR72">72</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 21 for BM = sub-group) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">NR for BM sub-group</P></TD> <TD align=3Dleft> <P class=3D"">Of 8 pts with measurable BM</P> <P class=3D"">Objective response in brain: 50%</P> <P class=3D"">(CR 0/8; PR 4/8)</P> <P class=3D"">(Stable disease 3/8</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival: = 3.9 months</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Hotta [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 14 for BM = sub-group) </P></TD> <TD align=3Dleft> <P class=3D"">NSCLC; data extracted for BM sub-group</P></TD> <TD align=3Dleft> <P class=3D"">NR for BM subgroup</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 43%</P> <P class=3D"">(CR 1/14, PR 5/14)</P> <P class=3D"">Stable disease 8/14</P> <P class=3D"">Objective response at extra-cranial sites: = 7/14</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Namba [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR69">69</A></CITE>]=20 (2004) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 15) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">8.3 months</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 60%</P> <P class=3D"">(CR 1/15; PR 8/15)</P> <P class=3D"">Stable disease 2/15</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Shimato [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR70">70</A></CITE>]=20 (2005) </P></TD> <TD align=3Dleft> <P class=3D"">Case series</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 8) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 5/8 pts</P> <P class=3D"">Of the 5 pts with an objective response:</P> <P class=3D"">3 pts classified as effective with gefitinib as = response was=20 in the setting of an uncontrollable BM or new BM after = radiotherapy</P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Wu [<CITE><A=20 = href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>]=20 (2007) </P></TD> <TD align=3Dleft> <P class=3D"">Prospective single arm phase II study</P> <P class=3D"">Evidence class III</P></TD> <TD align=3Dleft> <P class=3D"">Gefitinib (<I>n</I> =3D 40) </P></TD> <TD align=3Dleft> <P class=3D"">BM from NSCLC sub-type adenocarinoma</P></TD> <TD align=3Dleft> <P class=3D"">15 months</P></TD> <TD align=3Dleft> <P class=3D"">Objective response in brain: 38%</P> <P class=3D"">(CR 1/40; PR14/40)</P> <P class=3D"">Stable disease 18/40</P> <P class=3D"">Progressive disease 7/40</P></TD> <TD align=3Dleft> <P class=3D"">Median progression free survival:=20 9.0 months</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, <I>DR</I> = Distant=20 recurrence in brain, <I>ERC</I> Events review committee, <I>FdUrd</I>=20 5-fluoro-2′-deoxyuridine, <I>G1</I> Group 1, <I>G2</I> Group 2, = <I>G3</I> Group=20 3, <I>G4</I> Group 4, <I>LR</I> Local recurrence at original site in = brain,=20 <I>MGd</I> Motexafin-gadolinium, <I>NR</I> Not reported, <I>NS</I> Not=20 significant, <I>NSCLC</I> Non-small cell lung cancer, <I>OR</I> = Objective=20 response, <I>PR</I> Partial response, <I>Pts</I> Patients, <I>RCT</I> = Randomized=20 control trial, <I>SRS</I> Stereotactic radiosurgery, <I>TMZ</I> = Temozolomide,=20 <I>WBRT</I> Whole-brain radiation therapy </DIV></DIV></DIV></DIV></DIV> <P class=3D"">There is only class III evidence that a molecular targeted = agent,=20 gefitinib, results in partial response or stable disease in = approximately 80=9690%=20 of patients with brain metastases due to NSCLC. </P> <P class=3D"">Recent advances in the treatment of many malignancies have = frequently been due to the incorporation of molecular targeted agents = into the=20 treatment regimen. In NSCLC the two categories of molecular targeted = agents that=20 have received the most attention are agents targeting the epidermal = growth=20 factor or angiogenesis pathways [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR65">65</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR66">66</A></CITE>].=20 The use of RECIST criteria [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR67">67</A></CITE>]=20 to measure tumor response to these agents likely underestimates their=20 effectiveness since prolonged tumor stabilization has been noted with = these=20 agents. </P></DIV> <DIV class=3D""><A name=3DSec37></A> <DIV class=3DHeading3>Epidermal growth factor inhibiting agents</DIV> <P class=3D"">Gefitinib inhibits numerous tyrosine kinases, including = the=20 epidermal growth factor receptor (EGFR). It can be given orally and was = approved=20 for use in advanced NSCLC. Erlotinib is another widely used tyrosine = kinase=20 inhibitor of the EGFR receptor. Cetuximab is a monoclonal antibody to = the EGFR=20 receptor and is currently being evaluated in locally advanced and = advanced=20 NSCLC. </P> <P class=3D"">Table <A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#Tab5">5</A>=20 summarizes the case reports [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR70">70</A></CITE>]=20 and small single arm prospective studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR71">71</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>]=20 of gefitinib for patients with brain metastases from NSCLC. Most of = these have=20 demonstrated tumor response or stabilization in the majority of the = patients=20 treated. However, it is not generally used in patients as first line = treatment=20 for symptomatic brain metastases and there is no evidence that it should = be used=20 instead of WBRT or other conventional treatments [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR68">68</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR73">73</A></CITE>].=20 </P> <P class=3D"">An area of ongoing research is in the predictive value of = EGFR=20 mutations in NSCLC [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR74">74</A></CITE>].=20 In eight patients with brain metastases from lung cancer, Shimato et = al.,=20 reported the association of EGFR mutations with a higher rate of tumor=20 response/stabilization with gefitinib in a small number of patients. = Most of=20 these patients had previously undergone WBRT and this complicated the=20 attribution of tumor response or stabilization to gefitinib alone = [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR70">70</A></CITE>].=20 </P></DIV> <DIV class=3D""><A name=3DSec38></A> <DIV class=3DHeading3>Angiogenic-inhibiting agents</DIV> <P class=3D"">Agents targeting the angiogenesis pathway include = thalidomide and=20 bevacizumab. Bevacizumab is a monoclonal antibody against vascular = epidermal=20 growth factor receptor (VEGFR). Elevated VEGFR has been linked with = development=20 of brain metastases in murine models of NSCLC [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR75">75</A></CITE>].=20 There are no prospective studies of anti-angiogenesis agents for brain=20 metastases in humans in part due to concern regarding the possibility of = treatment-related intracranial bleeding. Prospective studies that have = shown a=20 survival benefit with bevacizumab in patients with non-squamous NSCLC = excluded=20 patients with known brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR76">76</A></CITE>].=20 A recently presented study by Akerly et al., concluded that the use of=20 bevacizumab along with cytotoxic chemotherapy agents resulted in only = one=20 central nervous system hemorrhage in a group of 85 patients with = non-small cell=20 carcinoma and known brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR77">77</A></CITE>].=20 More studies have been proposed to evaluate the safety of bevacizumab in = patients with brain metastases who undergo WBRT but no data meeting the = criteria=20 for inclusion in a recommendation are available. </P></DIV></DIV> <DIV class=3D""><A name=3DSec39></A> <HR> <DIV class=3Dheading2>Molecular targeted agent summary</DIV> <P class=3D"">The molecular underpinnings of tumor growth are better = understood=20 than ever in the past, but translation of this information to the = treatment of=20 brain metastases has not yet resulted in robust improvement in treatment = outcome=20 parameters. Isolated cases of treatment response have been observed with = epidermal growth factor inhibiting agents and angiogenic-inhibiting = agents. By=20 no means should agents related to epidermal growth factor or vascular=20 endothelial growth factor be viewed as the only candidates for the = targeted=20 therapies of brain metastases. Larger prospective and comparative = studies,=20 likely combined with more standard therapies, will be necessary to = determine if=20 such targeted agents will really contribute to tumor control and = improved=20 survival. </P></DIV> <DIV class=3D""><A name=3DSec40></A> <HR> <DIV class=3Dheading2>Investigational therapy summary</DIV> <P class=3D"">Not surprisingly, the clinical work done thus far with = newer=20 treatment modalities for metastatic brain tumors has not provided data = that=20 immediately translates into level 1 recommendations. Some progress has = been made=20 in defining the roll of TMZ in the management of brain metastases and it = is=20 clear that though there is a role it is limited as noted in the level 2=20 recommendation provided. Much of the clinical investigative work = completed and=20 published simply defines new problems and challenges with the techniques = and=20 agents that can be addressed in studies with properly asked questions. = Thus,=20 investigations to improve upon weaknesses identified in the above = discussion=20 continue to be reported. For example, demonstration of ongoing research = activity=20 for molecular targeted agents such as the assessment of gefitinib = efficacy, as=20 well as on a number of other fronts, is evidenced through reports at = national=20 meetings [<CITE><A=20 href=3D"http://www.springerlink.com/content/vw55868761322267/fulltext.htm= l#CR78">78</A></CITE>].=20 Even when no specific positive level 1 recommendations can be made, it = is still=20 appropriate to encourage enrollment in properly designed and conducted = clinical=20 trials of new treatment modalities and agents. </P></DIV> <DIV class=3D""><A name=3DSec41></A> <HR> <DIV class=3Dheading2>Key issues for future investigation</DIV> <P class=3D"">New modalities in the therapy of metastatic brain tumors = need not be=20 limited to the radiation therapy, radiation sensitizers, chemotherapy = and=20 molecular targeted agents mentioned in this guideline. Assessment of = alternative=20 types of radiation, improved radiation planning systems, improved = radiation and=20 chemotherapy targeting systems and assessment of other tumor metabolic = pathways=20 for targeting are critical to making progress against this broad ranging = disease. Enrollment of patients in properly conducted studies of each of = these=20 agents and modalities is warranted in order to learn their true value. = </P> <P class=3D"">Use of nanoparticle technology for identifying tumors, = targeting=20 therapy and assessing response early in therapy warrants particular = attention.=20 Investigation of other methods of molecular imaging, for instance with = MRI or=20 positron emission tomography, may result in better methods of early = detection of=20 therapeutic efficacy or failure helping to minimize time wasted on = ineffective=20 treatments. Improved radiation and systemic treatment planning and = targeting may=20 decrease toxicity to normal cerebral tissue improving quality of life = even=20 though disease control may not be impacted. </P> <P class=3D"">An exhaustive list of biologic issues that should be = addressed in=20 the therapy of cerebral metastases cannot be provided here but the = following=20 highlights should serve as inspiration to motivated investigators. = Though EGFR=20 and VEGFR are recognized as being important in many tumor types, they = are but=20 one avenue by which disordered molecular signaling provides = proliferative=20 advantage. Metastatic tumor cell resistance to standard alkylating = agents is yet=20 to be addressed effectively, especially in the central nervous system. = The=20 importance of tumor stem cells in metastatic brain lesions has yet to be = defined=20 in detail. Though the blood brain barrier is not generally an issue in = larger=20 brain metastases, the possibility of smaller clusters of cells with = growth=20 potential being shielded from therapy by this structure must be = investigated.=20 </P> <P class=3D"">The following is a list of major ongoing or recently = closed=20 randomized clinical trials pertaining to the use of emerging therapies = that=20 evaluate treatment comparisons addressed by this guideline paper for the = management of brain metastases. </P> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>Temozolomide for Treatment of Brain Metastases From Non-Small = Cell=20 Lung Cancer (Study P03247AM3) (COMPLETED)=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Randomized, Open-Label = Phase 2=20 Study of Temozolomide Added to Whole Brain Radiation Therapy = Versus Whole=20 Brain Radiation Therapy Alone for the Treatment of Brain = Metastasis From=20 Non-Small Cell Lung Cancer </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>: NCT00076856=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Not provided = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Not provided </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Schering-Plough = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>Study of Temozolomide in the Treatment of Brain Metastasis From=20 Non-Small-Cell Lung Cancer (Study P02143) (COMPLETED)=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase II Study of = Temozolomide (SCH=20 52365) in Subjects with Brain Metastasis from Non-Small-Cell Lung = Cancer=20 </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> NCT00034697=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Not provided = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Not provided </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Schering-Plough = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>Safety and Tolerability of Low-Dose Temozolomide During Whole = Brain=20 Radiation in Patients With Cerebral Metastases From Non-Small-Cell = Lung=20 Cancer (Study P04071) (TERMINATED)=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Randomized Phase II Study:=20 Temozolomide (TMZ) Concomitant to Radiotherapy Followed by = Sequential TMZ=20 in Advanced NSCLC Patients With CNS Metastasis Versus Radiotherapy = Alone=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Terminated (Phase II) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00266812=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Not provided = </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Not provided </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> = Schering-Plough, AESCA=20 Pharma GmbH </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>Radiation Therapy With or Without Temozolomide in Treating = Patients=20 With Non-Small Cell Lung Cancer That is Metastatic to the Brain=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase II Study Of = Temozolomide (SCH=20 52365) In Subjects With Brain Metastasis From Nonsmall Cell Lung = Cancer=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Active, not recruiting (Phase II)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00030836=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Lauren E. Abrey, = MD, Memorial=20 Sloan-Kettering 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> Memorial = Sloan-Kettering=20 Cancer Center, National Cancer Institute (NCI) = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>Temozolomide With or Without Radiation Therapy to the Brain in=20 Treating Patients With Stage IV Melanoma That Is Metastatic to the = Brain=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Temozolomide Versus=20 Temozolomide + Whole Brain Radiation In Stage IV = Melanoma=20 Patients With Asymptomatic 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> NCT00020839=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Juergen C. Becker, = MD, PhD=20 Universitaets-Hautklinik Wuerzburg </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 </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>6. </TD> <TD>Radiation Therapy Combined With Either Gefitinib or Temozolomide = in=20 Treating Patients With Non-Small Cell Lung Cancer and Brain = Metastases=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> Whole Brain Radiotherapy in = Combination With Gefitinib (Iressa) or Temozolomide (Temodal) for = Brain=20 Metastases From Non-Small Lung Cancer (NSCLC) A Randomized Phase = II Trial=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Status:</B> Recruiting (Phase II) </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Clinicaltrials.gov Identifier:</B> NCT00238251=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> Study Chair: = Gianfranco=20 Pesce, MD Oncology Institute of Southern Switzerland </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Investigator:</B> Roger Stupp, MD Centre = Hospitalier=20 Universitaire Vaudois </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Switzerland </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Swiss Group for = Clinical=20 Cancer Research </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>7. </TD> <TD>Radiation Therapy and Stereotactic Radiosurgery With or Without=20 Temozolomide or Erlotinib in Treating Patients With Brain = Metastases=20 Secondary to Non-Small Cell Lung Cancer=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase III Trial Comparing = Whole=20 Brain Radiation And Stereotactic Radiosurgery Alone Versus With=20 Temozolomide Or Erlotinib In Patients With Non-Small Cell Lung = Cancer And=20 1=963 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> NCT00096265=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigators:</B> </DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Paul Sperduto, MD, MAPP Park Nicollet Cancer=20 Center</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">Minesh P. Mehta, MD University of Wisconsin,=20 Madison</DIV></DIV> <DIV class=3DListPara> <DIV class=3D"">H. I. Robins, MD, PhD University of Wisconsin,=20 Madison</DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> United States and Canada (56 = locations)=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Radiation = Therapy=20 Oncology Group, National Cancer Institute (NCI) = </DIV></DIV></TD></TR> <TR vAlign=3Dtop> <TD>8. </TD> <TD>Comparison Study of WBRT and SRS Alone Versus With Temozolomide = or=20 Erlotinib in Patients With Brain Metastases of NSCLC=20 <DIV class=3DListPara> <DIV class=3D""><B>Official title:</B> A Phase III Trial Comparing = Whole=20 Brain Radiation (WBRT) and Stereotactic Radiosurgery (SRS) Alone = Versus=20 With Temozolomide or Erlotinib in Patients With Non-Small Cell = Lung Cancer=20 and 1=963 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> NCT00268684=20 </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Principal Investigator:</B> Felix Bokstein, = M.D. Tel-Aviv=20 Sourasky Medical Center </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Location:</B> Israel </DIV></DIV> <DIV class=3DListPara> <DIV class=3D""><B>Sponsors and Collaborators:</B> Tel-Aviv = Sourasky Medical=20 Center, RTOG = </DIV></DIV></TD></TR></TBODY></TABLE></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. The = editorial=20 assistance of Emily Feinstein is appreciated.</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>Robinson PD, Kalkanis SN, Linskey ME, = Santaguida PL=20 (2009) Methodology used to develop the AANS/CNS management of = brain=20 metastases evidence-based clinical practice parameter guidelines. = J=20 Neurooncol. doi:<A=20 = href=3D"http://dx.doi.org/10.1007/s11060-009-0059-2">10.1007/s11060-009-0= 059-2</A>=20 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Centre for Evidence-Based Physiotherapy (2009) = Physiotherapy evidence database (PEDro). <A=20 href=3D"http://www.pedro.org.au/">http://www.pedro.org.au/</A>. = Accessed Jan=20 2009 </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>3.</TD> <TD><A name=3DCR3></A>Maher CG, Sherrington C, Herbert RD, Moseley = AM,=20 Elkins M (2003) Reliability of the PEDro scale for rating quality = of=20 randomized controlled trials. 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