10.1007/s11060-009-0062-7</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/s11060-009-0062-7</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of chemotherapy in = the management=20 of newly diagnosed brain metastases: a systematic review and = evidence-based=20 clinical practice guideline </DIV> <P class=3DAuthorGroup>Minesh P. Mehta<SUP>1</SUP>,=20 Nina A. Paleologos<SUP>2</SUP>, = Tom Mikkelsen<SUP>3</SUP>,=20 Paula D. Robinson<SUP>4</SUP>, = Mario Ammirati<SUP>5</SUP>,=20 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 Laurie E. Gaspar<SUP>10</SUP>, = Douglas Kondziolka<SUP>11</SUP>,=20 Mark E. Linskey<SUP>12</SUP>, = Jay S. Loeffler<SUP>13</SUP>,=20 Michael McDermott<SUP>14</SUP>, = Jeffrey J. Olson<SUP>15</SUP>,=20 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/m42x58l615326720/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/m42x58l615326720/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 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=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 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=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 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=3DAff11></A>(11) </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=3DAff12></A>(12) </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=3DAff13></A>(13) </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=3DAff14></A>(14) </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=3DAff15></A>(15) </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=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, Hermelin = Brain=20 Tumor Center, Henry Ford Health System, 2799 West Grand Blvd, = K-11,=20 Detroit, MI 48202, USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor18></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/m42x58l615326720/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:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>7 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>4 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A = name=3DASec1></A>Target=20 population </SPAN>This recommendation applies to adults with = newly=20 diagnosed brain metastases; however, the recommendation below does not = apply to=20 the exquisitely chemosensitive tumors, such as germinomas metastatic to = the=20 brain. </DIV></DIV> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec2></A>Recommendation </SPAN> <B>Should patients = with brain=20 metastases receive chemotherapy in addition to whole brain radiotherapy=20 (WBRT)?</B>=20 <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Level 1</I></B> Routine use of chemotherapy = following WBRT=20 for brain metastases has not been shown to increase survival and is not=20 recommended. Four class I studies examined the role of carboplatin,=20 chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in = no=20 survival benefit. Two caveats are provided in order to allow the = treating=20 physician to individualize decision-making: First, the majority of the = data are=20 limited to non small cell lung (NSCLC) and breast cancer; therefore, in = other=20 tumor histologies, the possibility of clinical benefit cannot be = absolutely=20 ruled out. Second, the addition of chemotherapy to WBRT improved = response rates=20 in some, but not all trials; response rate was not the primary endpoint = in most=20 of these trials and end-point assessment was non-centralized, = non-blinded, and=20 post-hoc. Enrollment in chemotherapy-related clinical trials is = encouraged.=20 </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Chemotherapy - Whole brain radiation=20 therapy - Targeted agents - Systematic=20 review - Practice guideline </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">Brain metastases are a common complication of systemic = cancer,=20 occurring in 20=9640% of patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR1">1</A></CITE>].=20 The primary therapeutic approach for disseminated systemic disease = remains=20 chemotherapy, and therefore, one might expect this to be a logical = choice for=20 brain metastases as well. However, several issues have limited the = application=20 of chemotherapy in this context. One concern involves the ability of=20 chemotherapeutic agents to cross the blood=96brain barrier (BBB). Many=20 chemotherapeutic agents are relatively excluded from the brain, and ones = that do=20 penetrate, may do so in insufficient concentrations. Although there is = relative=20 breakdown of the BBB in and around a metastatic lesion in the brain, = some=20 studies have demonstrated that there is still only very limited drug=20 concentration within the lesion. Recent findings suggest that efflux = pumps may=20 play a major role in this phenomenon [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR2">2</A></CITE>].=20 Some animal studies have shown that if metastatic tumors enhance = strongly on=20 computed tomography (CT) or magnetic resonance imaging (MRI), that the=20 blood=96brain barrier (BBB) is sufficiently impaired to allow entry of=20 chemotherapeutic drugs. Newer agents which cross the BBB have and are = being=20 developed as well. New molecular based therapies directed against growth = factor=20 receptors and other protein kinases are being investigated, however = their large=20 size also raises concerns about penetrability. There is also the = long-standing=20 observation that intracranial response rates to chemotherapy are = typically lower=20 than in the extracranial compartment, and a common hypothesis for this = finding=20 is that patients are pre-exposed to cytotoxic therapies, and it is the=20 chemoresistant clones that metastasize to the brain. However, data in = newly=20 diagnosed, previously untreated patients with small cell lung cancer = (SCLC)=20 suggest that intracranial response rates remain significantly lower than = extracranial response rates, thereby suggesting that chemoresistant = clones alone=20 do not necessarily explain this dichotomy [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR3">3</A></CITE>].=20 Some types of metastatic brain tumors may respond to chemotherapy to = some=20 degree, including breast cancer, germ cell cancer, and ovarian cancer in = addition to SCLC. </P> <DIV class=3DPara> <DIV class=3D"">The use of chemotherapy for brain metastases has been = explored in=20 four primary contexts:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>WBRT vs. WBRT plus chemotherapy</TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>Chemotherapy vs. chemotherapy plus WBRT</TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>Chemotherapy plus concurrent WBRT vs. chemotherapy plus delayed=20 WBRT</TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>Chemotherapy first, followed by WBRT vs. WBRT first, followed by = chemotherapy</TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <P class=3D"">To answer the above question and its subparts, a = comprehensive=20 systematic literature review was performed.</P> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane = Database=20 of Abstracts of Reviews of Effects. A broad search strategy using a = combination=20 of subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR4">4</A></CITE>]=20 Reference lists of included studies were also reviewed. </P> <DIV class=3DPara> <DIV class=3D"">For inclusion in this analysis, the following criteria = had to be=20 met:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English with a publication date of 1990 = forward.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with newly diagnosed brain metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully published peer-reviewed primary comparative studies (all=20 comparative study designs for primary data collection included; = e.g., RCT,=20 non-randomized trials, cohort studies or case=96control studies). = </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Any comparative studies evaluating chemotherapy alone or in=20 combination with other treatment modalities for the treatment of = newly=20 diagnosed brain metastases. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with newly diagnosed brain = metastases ≥5=20 per study arm for at least two of the study arms.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Baseline information on study participants is provided by = treatment=20 group in studies evaluating interventions exclusively in patients = with=20 newly diagnosed brain metastases. For studies with mixed = populations=20 (i.e., includes participants with conditions other than newly = diagnosed=20 brain metastases), baseline information is provided for the = intervention=20 sub-groups of participants with newly diagnosed brain metastases.=20 </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec4></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/m42x58l615326720/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR6">6</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=3DSec5></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper for this guideline = series.=20 </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">The literature search resulted in the identification of = 16,966=20 citations of which 16,936 were eliminated at abstract review as not = having=20 relevance to the specific question. The remaining 30 studies were = subject to=20 full text screening, and 20 were excluded, seven because they lacked = baseline=20 patient data by treatment group, 10 because they lacked baseline patient = subset=20 data by treatment group, two because there was no treatment comparison = of=20 interest, and one because it was not a comparative study. Ten eligible = studies=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>]=20 were therefore fully reviewed and form the basis of this report (see=20 Table <A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#Tab1">1</A>;=20 Fig. <A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#Fig1">1</A>).<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Summary = of primary=20 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""><I>WBRT vs. WBRT + chemotherapy</I> = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Guerrieri (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 21) </P> <P class=3D"">G2: WBRT + Carboplatin = (<I>n</I> =3D 21)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.4 months</P> <P class=3D"">G2: 3.7 months (survival curves: log-rank;=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of evaluable pts)</P> <P class=3D"">G1: OR 10% (of 11 pts assessed)</P> <P class=3D"">G2: OR 29% (of 16 pts assessed) = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Ushio (1991) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR8">8</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 25) </P> <P class=3D"">G2: WBRT + Chloroethylnitrosoureas=20 (<I>n</I> =3D 34) </P> <P class=3D"">G3:=20 WBRT + Chloroethylnirosoureas + Tegafur=20 (<I>n</I> =3D 29) </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from lung cancer</P></TD> <TD align=3Dleft> <P class=3D"">G1: 27 weeks</P> <P class=3D"">G2: 29 weeks</P> <P class=3D"">G3: 30.5 weeks (survival curves: Wilcoxon;=20 <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 36% (CR 4/14, PR 1/14)</P> <P class=3D"">G2: OR 69% (CR 11/16, PR 0/16)</P> <P class=3D"">G3: OR 74% (CR 12/19, PR 2/19)</P> <P class=3D"">G1 vs. G2 (<I>P</I> =3D NS) </P> <P class=3D"">G2 vs. G3 (<I>P</I> =3D NS) </P> <P class=3D"">G1 vs. G3 (<I>P</I> < 0.05) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Antonadou (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR9">9</A></CITE>]=20 </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"">Pts with 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 (survival curves: log-rank;=20 <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"">Verger (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR10">10</A></CITE>]=20 </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"">Pts with BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 3.1 months</P> <P class=3D"">G2: 4.5 months (survival curves: log-rank;=20 <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"">Kim (2005) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 32) </P> <P class=3D"">G2: WBRT + platinum-based chemotherapy=20 (<I>n</I> =3D 31) </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM at diagnosis of NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 19.0 weeks</P> <P class=3D"">G2: 58.1 weeks (survival curves: test not = specified:=20 <I>P</I> < 0.001) </P></TD> <TD align=3Dleft> <P class=3D"">No comparison between groups</P></TD> <TD align=3Dleft> <P class=3D"">No comparison between groups</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D""><I>Chemotherapy vs. = chemotherapy + WBRT</I>=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Mornex (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR12">12</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: 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"">Pts with BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 86 days</P> <P class=3D"">G2: 105 days (survival curves: log-rank;=20 <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 (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"">Postmus (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR13">13</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: Teniposide (<I>n</I> =3D 60) </P> <P class=3D"">G2: Teniposide + WBRT = (<I>n</I> =3D 60)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from SCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 3.2 months</P> <P class=3D"">G2: 3.5 months (survival curves: log-rank;=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (by ITT)</P> <P class=3D"">G1: OR 22% (CR 5/60, PR 8/60)</P> <P class=3D"">G2: OR 57% (CR 18/60, PR 16/60)=20 (<I>P</I> < 0.001) </P> <P class=3D"">Response rate outside the brain:</P> <P class=3D"">G1: OR 20% (CR 3/60, PR 9/60)</P> <P class=3D"">G2: OR 33% (CR 6/60, PR 14/60) = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression in brain: NR</P> <P class=3D"">Significant difference in favor of G2 (BM = progression-free=20 curves: log-rank; <I>P</I> =3D 0.005) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Moscetti (2006) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR14">14</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: Platinum-based chemotherapy = (<I>n</I> =3D 110)=20 </P> <P class=3D"">G2: WBRT + chemotherapy = (<I>n</I> =3D 46)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM at diagnosis of NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 10 months</P> <P class=3D"">G2: 14 months (survival curves: test not = specified;=20 <I>P</I> =3D 0.07; NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (OR by ITT)</P> <P class=3D"">G1: OR 27.3% (CR 15/107, PR 15/107)</P> <P class=3D"">G2: OR 34.8% (CR 2/46, PR 14/46) = (<I>P</I> =3D NS)=20 </P> <P class=3D"">Extra-cranial response rate:</P> <P class=3D"">G1: OR 34.5% (CR 0/107, PR 38/107)</P> <P class=3D"">G2: OR 41.3% (CR 0/46, PR 19/46) = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival:</P> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 6 months (Progression-free curves: test not = specified; <I>P</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D""><I>Chemotherapy + concurrent WBRT vs.=20 chemotherapy + delayed WBRT</I> </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Robinet (1998) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR15">15</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: = Cisplatin + vinorelbine + delayed WBRT=20 (<I>n</I> =3D 86) </P> <P class=3D"">G2: = Cisplatin + vinorelbine + concurrent=20 WBRT (<I>n</I> =3D 85) </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 24 weeks</P> <P class=3D"">G2: 21 weeks (survival curves: log-rank;=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (by ITT)</P> <P class=3D"">G1: OR 27% (CR 1/76, PR 22/76)</P> <P class=3D"">G2: OR 33% (CR 7/73, PR 21/73) = (<I>P</I> =3D NS) </P> <P class=3D"">Extra-cranial rate response:</P> <P class=3D"">G1: OR 35% (CR 2/76, PR 28/76)</P> <P class=3D"">G2: OR 25% (CR 2/73, PR 19/73) = (<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: 13 weeks</P> <P class=3D"">G2: 11 weeks (BM progression-free curves: = log-rank;=20 <I>P</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D""><I>WBRT + delayed chemotherapy vs.=20 chemotherapy + delayed WBRT</I> </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lee (2008) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: Chemotherapy followed by WBRT = (<I>n</I> =3D 25)=20 </P> <P class=3D"">G2: WBRT followed by chemotherapy = (<I>n</I> =3D 23)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9.1 months</P> <P class=3D"">G2: 9.9 months (survival curves; log-rank:=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Overall response in brain:</P> <P class=3D"">G1: PR 7/25, SD 10/25, PD 8/25</P> <P class=3D"">G2: PR 9/23, SD 4/23, PD 6/23 = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Progression free survival:</P> <P class=3D"">G1: 3.6 months</P> <P class=3D"">G2: 4.4 months (<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>G1</I> = group 1,=20 <I>G2</I> group 2, <I>G3</I> group 3, <I>G4</I> group 4, <I>ITT</I>=20 intention-to-treat, <I>NR</I> not reported, <I>NS</I> not significant,=20 <I>NSCLC</I> non-small cell lung cancer, <I>OR</I> objective response, = <I>PD</I>=20 progressive disease, <I>PR</I> partial response, <I>Pts</I> patients, = <I>RCT</I>=20 randomized control trial, <I>SCLC</I> small-cell lung cancer, <I>SD</I> = stable=20 disease, <I>TMZ</I> temozolomide; <I>WBRT</I> whole-brain radiation = therapy=20 </DIV></DIV></DIV> <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_62_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/m42x58l615326720/MediaObjects/= 11060_2009_62_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV class=3D"">These 10 studies were assigned to the four sub-questions = above as=20 follows:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD> </TD> <TD>WBRT vs. WBRT + chemotherapy: 5 studies [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>].=20 </TD></TR> <TR vAlign=3Dtop> <TD> </TD> <TD>Chemotherapy vs. chemotherapy + WBRT: 3 studies = [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR17">17</A></CITE>].=20 </TD></TR> <TR vAlign=3Dtop> <TD> </TD> <TD>Chemotherapy + concurrent WBRT vs.=20 chemotherapy + delayed WBRT: 1 study [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR15">15</A></CITE>].=20 </TD></TR> <TR vAlign=3Dtop> <TD> </TD> <TD>Chemotherapy first, followed by WBRT vs. WBRT first, followed by = chemotherapy: 1 study [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>].=20 </TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Clearly, the role of chemotherapy in the management of = brain=20 metastases has been explored in a very limited number of controlled = comparative=20 trials, and therefore the class of evidence and hence the level of=20 recommendations have limited applicability. In addition, outcome = parameters vary=20 between the studies, further complicating direct comparisons; = nonetheless, these=20 studies do provide important information regarding the endpoints of = survival,=20 tumor response to therapy, and time to progression for specific clinical = scenarios. Further, we must also acknowledge that these recommendations = do not=20 apply to the exquisitely chemosensitive tumors, such as germinomas = metastatic to=20 the brain. Finally, although many targeted agents hold some promise in = the=20 management of metastatic disease to the brain, controlled comparative = trials are=20 just beginning to be conducted, and the data are not sufficiently mature = to be=20 included in this analysis. Refer to Table <A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#Tab1">1</A>=20 for details of the included studies. </P></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>WBRT vs. WBRT plus chemotherapy</DIV> <P class=3D"">Five studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>]=20 met the inclusion criteria for this sub-question. Four of five studies = provide=20 class I evidence (two are phase III randomized trials, and two are = randomized=20 phase II trials) and the fifth is a retrospective cohort study, = providing, at=20 best, class II evidence. </P> <P class=3D"">In 2004 Guerrieri et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>]=20 published a multi-institutional, randomized controlled trial (RCT) of = palliative=20 radiation with concomitant carboplatin for patients with brain = metastases from=20 NSCLC, with overall survival as the primary endpoint. Patients with=20 histologically or cytologically proven NSCLC, with ≥1 brain = metastases=20 identified by CT or MRI, deemed either inoperable or who refused = surgery, with a=20 WHO performance status of 0, 1 or 2, and who had adequate laboratory = parameters=20 were included. Prior chemotherapy or brain radiotherapy were exclusion = criteria.=20 Patients were stratified by institution. Forty-two patients were = randomized to=20 two groups, G1: WBRT (<I>n</I> =3D 21) G2: = WBRT + Carboplatin=20 (<I>n</I> =3D 21). The radiotherapy dose was 20 Gy in 5 = fractions=20 in both arms and the Carboplatin dose was 70 mg/m<SUP>2</SUP> = IV/day =D7=20 5 days. The detailed demographic breakdown is presented in the = tabular=20 summary. Patients were well-balanced between the two arms by age, = gender,=20 histology, and number of brain lesions; the status of extra-cranial = disease was=20 not reported. There was a mismatch in terms of WHO performance status = between=20 the two groups; there were 33% vs. 67% PS 1 patients in G1 vs. G2, and = 52% vs.=20 19% PS 2 patients in G1 vs. G2. Additionally, in G1, 24% of patients had = a=20 neurologic function status of 3, compared to 5% in G2. Median follow-up = was not=20 reported. The degree of steroid usage in each of the two groups was not=20 reported. The trial was terminated early due to low patient accrual, = thus=20 limiting the ability to draw statistically significant conclusions. </P> <P class=3D"">The median survival was comparable, 4.4 vs. = 3.7 months for G1=20 vs. G2, which was statistically not significant. Overall response was = reported=20 in a subset of patients. Of 11 assessed patients in G1, the OR was 10%, = compared=20 to 29% in 16 patients in G2, which was statistically not significantly=20 different; however, when patients were compared in terms of WHO = performance=20 status compared to pre-treatment, 14% in G1 were worse, and 57% in G2 = were=20 worse; similarly, in terms of neurological function status compared to=20 pre-treatment, 10% were worse in G1, compared to 38% in G2. Although WHO = performance and neurologic function deterioration were more common in = G2, there=20 were no significant differences in gastrointestinal or hematological = toxicities=20 between the groups. </P> <P class=3D"">This trial, with incomplete accrual, failed to meet the = primary=20 objective of demonstrating improved survival with the addition of = carboplatin to=20 WBRT in NSCLC patients with brain metastases. While designed as a class = I study,=20 the aforementioned concerns regarding this trial may further limit its = impact=20 when making treatment recommendations, as no statistically significant=20 differences in survival were noted between the groups. However, the = study does=20 appear to support the use of chemotherapy when secondary endpoints such = as=20 response rate are analyzed. </P> <P class=3D"">The second major RCT, also designed as a class I study, = was reported=20 by Ushio et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR8">8</A></CITE>]=20 in 1991. Patients with a diagnosis of brain metastases from lung cancer = with the=20 primary lesion and/or systemic lesions relatively well controlled, and a = projected survival of >4 months, were enrolled. Previous = chemotherapy=20 with any of the drugs used in this study was an exclusion factor. = Patients were=20 randomized to three groups: G1: WBRT alone (<I>n</I> =3D 25), = G2:=20 WBRT + Chloroethylnitrosoureas (either methyl-CCNU or ACNU)=20 (<I>n</I> =3D 34), G3:=20 WBRT + Tegafur + Chloroethylnitrosoureas=20 (<I>n</I> =3D 29). In all three groups, surgery was permitted = prior to=20 WBRT, if the lesions could be removed without neurologic deficits. The = WBRT dose=20 was 40 Gy in 1.5=962 Gy fractions; the methyl-CCNU dose was=20 100=96120 mg/m<SUP>2</SUP> orally every 6=968 weeks (at = midpoint in the=20 study, methyl-CCNU became unavailable and was replaced with ACNU=20 80=96100 mg/m<SUP>2</SUP> IV every 6=968 weeks) and the = Tegafur dose was=20 300 mg/m<SUP>2</SUP>/day given orally. Patients were well balanced = in all=20 three groups by gender, age, histology, and number of brain metastases. = The=20 status of extra-cranial disease, the degree of corticosteroid use, and = baseline=20 functional performance score was not reported, and median follow-up of = patients=20 was not available. </P> <P class=3D"">The primary endpoint was tumor control, but median = survival was also=20 analyzed. There was no statistically significant difference in survival = between=20 the three arms (27, 29, and 30.5 weeks for G1, G2 and G3 = respectively).=20 Intracranial response analysis revealed an overall response rate of 36, = 69, and=20 74% for groups 1=963, respectively. When the response rate for group 1 = was=20 statistically compared to that of group 3, it reached statistical = significance,=20 with a <I>P</I> < 0.05 (overall response rate: 36 vs. 74%; = the=20 comparable complete response rates for the two groups were four of 14 = patients=20 vs. 12 of 19 patients). Functional performance outcome was not reported = nor was=20 the time to intracranial recurrence/progression. The causes of death = were=20 ascertained, and the rate of neurologic death was 3/25 in G1, 0/32 in G2 = and=20 4/28 in G3. Adverse events were not reported in detail in the study; = however two=20 patients were thought to have died from the effects of chemotherapy (one = from=20 pancytopenia and one from cardiac failure). </P> <P class=3D"">In summary, this RCT of 88 patients did not show a = survival=20 improvement with the addition of chemotherapy, but showed a = statistically=20 significant improvement in response rates, especially the rates of = complete=20 response, with the addition of Tegafur and a nitrosourea to WBRT in = patients=20 with NSCLC. </P> <P class=3D"">In 2002, Antonadou et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR9">9</A></CITE>]=20 reported on a phase II RCT in which patients with brain metastases were=20 randomized to WBRT alone or WBRT plus temozolomide. Adult patients aged = 18 or=20 older, with brain metastases from histologically proven cancer of the = lung,=20 breast, or unknown primary, with a performance status ≤2, life = expectancy=20 ≥3 months, and adequate hematologic, renal, hepatic function, = were=20 included. Exclusion factors were previous chemotherapy or radiotherapy = for brain=20 metastases, or any uncontrollable, life-threatening systemic disease, or = pregnant or lactating women. Patients (<I>n</I> =3D 23) in = group 1=20 received 40 Gy of WBRT in 20 fractions of 2 Gy each. In group = 2,=20 (<I>n</I> =3D 25) patients received the same dose of WBRT with = 75 mg/m<SUP>2</SUP>/day of temozolomide orally during WBRT and = continued=20 temozolomide therapy (200 mg/m<SUP>2</SUP>/day for 5 days = every=20 28 days for an additional 6 cycles after WBRT. The median follow-up = time=20 was 4 months. The groups were well-balanced with respect to gender, = age,=20 baseline performance status, neurologic functional level, and tumor = type, with=20 65% of patients having NSCLC, as well as number of brain metastases and = presence=20 of extracranial disease. </P> <P class=3D"">The primary study endpoints were radiologic response and = neurologic=20 symptom evaluation. Survival was also analyzed. The median survival was = 7 vs.=20 8.6 months for G1 vs. G2 (not statistically significant). The = overall=20 response rate was 67% vs. 96% for G1 vs.G2, with a = <I>P</I> =3D 0.017=20 which was statistically significant. The time to recurrence or = progression of=20 disease in the brain, and also the cause of death were not reported. = There was=20 neurologic improvement in the group receiving temozolomide, and fewer = patients=20 required corticosteroids after treatment in the temozolomide group = compared with=20 radiotherapy alone. The temozolomide was generally well tolerated with = some=20 toxicities statistically more common in that group, including nausea, = and=20 vomiting. Hematologic toxicity was reversible. </P> <P class=3D"">In summary, this RCT of 48 patients did not show a = survival=20 improvement with the addition of temozolomide chemotherapy, but showed a = statistically significant improvement in response rates and an = improvement in=20 neurologic function with the addition of temozolomide to WBRT, which = constitutes=20 class I evidence. We are aware of a subsequent larger randomized trial = performed=20 by the same group, but this has never been published in manuscript form = and is=20 therefore not available as a peer-reviewed literature item. </P> <P class=3D"">In 2003, Verger et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR10">10</A></CITE>]=20 reported on a phase II RCT in patients with brain metastases randomized = to WBRT=20 alone or WBRT plus temozolomide. Adult patients aged 18 or older, with = brain=20 metastases from histologically proven cancer, unsuitable for surgery or = SRS,=20 with a Karnofsky performance score (KPS) ≥50, and adequate = hematologic, renal,=20 and hepatic function, were included. Exclusion factors included previous = chemotherapy within the previous 3 weeks, prior cranial = radiotherapy,=20 leptomeningeal involvement, intratumoral hemorrhage, and clinical or = psychiatric=20 conditions that would interfere with completion or required evaluations. = </P> <P class=3D"">Stratification variables included age, KPS and type of = primary=20 tumor. Patients (<I>n</I> =3D 41) in G1 received 30 Gy = WBRT in 10=20 fractions of 3 Gy. In G2, 41 patients received the same dose of = WBRT with=20 75 mg/m<SUP>2</SUP>/day of temozolomide orally during WBRT and = continued=20 temozolomide therapy (150=96200 mg/m<SUP>2</SUP>/day for = 5 days every=20 28 days for an additional 2 cycles after WBRT.) The median = follow-up time=20 was not reported. The groups were well-balanced with respect to gender, = age,=20 baseline performance status, tumor type (with 53 and 49% of patients = having=20 NSCLC), number of brain metastases and presence of extracranial disease. = </P> <P class=3D"">Unlike in the other studies mentioned above, the primary = outcome in=20 this trial was an analysis of neurologic toxicity. Radiologic response = and=20 progression free survival were also analyzed secondarily. The trial was = stopped=20 prematurely due to low patient accrual. The median survival was 3.1 vs.=20 4.5 months for G1 vs. G2 and was not statistically significant. The = overall=20 response at day 30 was 32% for both G1 and G2. At 90 days, the = radiologic=20 response could only be assessed in 35 patients and was similar in the = two=20 groups. Freedom from intracranial progression at 90 days was 54 vs. = 72%=20 (<I>P</I> =3D 0.03) in favor of the WBRT plus temozolomide = group.=20 Functional performance change was not reported. There was a = statistically=20 significant difference in cause of death between the two groups, with = neurologic=20 death occurring in 69% in G1 compared to 41% in G2 = (<I>P</I> =3D 0.029)=20 again favoring the WBRT plus temozolomide group. No acute neurologic = toxicity=20 developed in the WBRT plus temozolomide arm and temozolomide did not = interfere=20 with delivery of WBRT. </P> <P class=3D"">In summary, this prematurely terminated RCT of 82 = patients, which=20 was designed as a class I study, did not show either a survival = improvement with=20 the addition of temozolomide chemotherapy, or statistically significant=20 improvement in response rates, with the addition of temozolomide to = WBRT.=20 Although insufficient to support a level 1 recommendation, the evidence = in this=20 study did show an improvement with the addition of chemotherapy in the = secondary=20 endpoints of intracranial progression and neurologic death. </P> <P class=3D"">Finally, in 2005, Kim et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>]=20 published a retrospective cohort study which included NSCLC patients = with=20 synchronous brain metastases who received WBRT for intracranial lesions = found=20 during evaluation of neurologic symptoms. The exclusion criteria were = patients=20 who did not receive WBRT, leptomeningeal carcinomatosis, Eastern = Cooperative=20 Oncology Group (ECOG) performance status of grade 3 or 4, surgical = resection or=20 radiotherapy for thoracic lesions, or open surgical removal of = intracranial=20 metastatic lesions. The interventions included G1: WBRT=20 (<I>n</I> =3D 32) and G2: WBRT + platinum-based = chemotherapy=20 (<I>n</I> =3D 31). The WBRT dose was 30 to 40 Gy, and = several=20 platinum doublets were employed. </P> <P class=3D"">The median follow-up was not reported. The groups were = well balanced=20 in terms of gender, age, tumor type (100% NSCLC), number of brain = metastases,=20 presence of extracranial disease, and baseline performance score. The = primary=20 outcome was not specified, but there was a marked difference in median = survival,=20 G1: 19.0 weeks vs. G2: 58.1 weeks = (<I>P</I> < 0.001). No=20 data were presented regarding tumor control, time to intracranial = recurrence, or=20 cause of death. The neurologic response was not significantly different = between=20 the two groups. </P> <P class=3D"">In summary, this non-randomized cohort study of 63 = patients showed a=20 survival improvement with the addition of various platinum-based doublet = chemotherapies in addition to WBRT. This constitutes class II evidence. = There=20 was no improvement in secondary endpoints. </P></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Chemotherapy vs. chemotherapy plus WBRT</DIV> <P class=3D"">In 2003, Mornex et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR12">12</A></CITE>]=20 published results of a prospective randomized phase III trial of = fotemustine=20 plus WBRT (<I>n</I> =3D 37) versus fotemustine alone=20 (<I>n</I> =3D 39) in patients with cerebral metastases from = malignant=20 melanoma. The main objectives were objective response and time to = cerebral=20 progression. Patients with histologically confirmed malignant melanoma = with at=20 least one non-resectable metastasis and who fit other parameters were = included.=20 Patients were required to have received no chemotherapy in the prior=20 4 weeks, no previous nitrosourea-based chemotherapy and no previous = cerebral radiotherapy. Both arms were well balanced with respect to the = number=20 of cerebral metastases, extent of visceral disease and age. Patients in = the=20 fotemustine alone arm had worse baseline performance status (ECOG 2=963 = 54%=20 compared to 30% in the fotemustine plus WBRT group) and had been treated = with=20 more chemoimmunotherapy (59 versus 32% respectively). Additionally, the = median=20 time interval between the primary diagnosis and the onset of brain = metastases=20 was different between the two groups (550 days for the fotemustine = alone=20 group and 1131 days for the fotemustine + WBRT group). = The dose=20 of WBRT was 37.5 Gy in 15 fractions over 3 weeks. Fotemustine = was=20 given intravenously at 100 mg/m<SUP>2</SUP> on days 1, 8 and 15, = followed=20 by a 5 week rest period and then every 3 weeks in = non-progressing=20 patients. Although the fotemustine alone patients had worse prognostic = factors,=20 there was no difference in cerebral response or control or in overall = survival=20 (86 days in the fotemustine group vs. 105 days in the combined = treatment group). There was a statistically significant difference in = time to=20 cerebral progression favoring the WBRT + fotemustine group=20 (<I>P</I> =3D 0.028) with that group having a median time to = objective=20 cerebral progression of 56 days compared to 49 days in the=20 chemotherapy alone group. This constitutes class I evidence. </P> <P class=3D"">A phase III randomized study comparing teniposide (G1) = versus=20 teniposide with WBRT (G2) in patients with brain metastases from SCLC = was=20 reported by Postmus et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR13">13</A></CITE>]=20 in 2000. Their stated goal was to evaluate the role of WBRT in SCLC = patients=20 with brain metastases. The primary end point was survival. Teniposide = was=20 administered intravenously at 120 mg/m<SUP>2</SUP> on days 1, 3, = and 5=20 every 3 weeks up to a maximum of 12 courses or until disease = progression=20 either inside or outside the brain. WBRT, dosed at 30 Gy in 10 = fractions=20 over 2 weeks, had to be started within 3 weeks of the start of = treatment with teniposide. Dexamethasone dosing parameters were = outlined. Of the=20 134 patients randomized, 120 were eligible (60 in each group). The = groups were=20 well matched for age, ECOG performance status, neurologic function and = number of=20 brain metastases. Although the response rate in the combined modality = group (G2)=20 was significantly higher (57%) than in the teniposide alone group (G1) = (22%),=20 this did not result in a prolongation of overall survival, thought to be = due to=20 progression of disease outside the brain (3.2 months in G1 and=20 3.5 months in G2). Time to progression in the brain was assessed by = CT scan=20 rather than MRI in this European study and was significantly longer in = the=20 combined modality group. This RCT constitutes class I evidence. </P> <P class=3D"">In a retrospective cohort study, Moscetti et al. [<CITE><A = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR14">14</A></CITE>]=20 analyzed 110 patients (G1) with newly diagnosed NSCLC with brain = metastases who=20 had received up-front platinum-based chemotherapy and 46 patients who = had=20 received WBRT followed by chemotherapy (G2). The authors sought to = analyze the=20 process by which six oncologic centers guided the pattern of care. In = this=20 survey of unselected patients, choice of treatment appeared guided by = presence=20 of neurologic symptoms from the brain metastases. The response rate in = the brain=20 was 27.3% in G1 and 34.8% in G2 with no significant difference in median = time to=20 progression in the brain (6 months in both groups). With regard to = the=20 first treatment option, the median survival was 10 months for G1 = and=20 14 months for G2. While this study does show that some patients = with brain=20 metastases from NSCLC will respond initially to platinum-based = chemotherapy,=20 there are too many variables in the patient cohorts and reasons for = treatment=20 choice to derive any meaningful data for recommendation. This = retrospective=20 study constitutes class II evidence. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Chemotherapy with concomitant WBRT vs. = chemotherapy with=20 delayed WBRT</DIV> <P class=3D"">Robinet et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR15">15</A></CITE>]=20 published a randomized trial in 1998 evaluating the use of systemic = chemotherapy=20 for the treatment of inoperable brain metastases from NSCLC with early = WBRT=20 versus WBRT delayed until progression. They treated 85 patients with = cisplatin=20 and vinorelbine used concurrently with WBRT and 86 treated with the same = chemotherapy, but with WBRT delayed for at least 2 cycles. No WBRT-alone = group=20 was included. Patients had histologically verified NSCLC and at least = one brain=20 metastasis >10 mm in diameter. Patients had an acceptable = performance=20 status and good end-organ function. Patients were treated with cisplatin = 100 mg/m<SUP>2</SUP> on day 1, vinorelbine 30 mg/m<SUP>2</SUP> = on days=20 1, 8, 15 and 22, with cycles repeated every 4 weeks. In one group,=20 chemotherapy was started concurrent with WBRT, administered as = 30 Gy in 10=20 fractions of 3 Gy given over 2 weeks. In the other group, = radiation=20 was deferred. </P> <P class=3D"">Median follow-up was not reported, but 171 patients were = accrued and=20 the two treatment groups were balanced with regard to age, sex, tumor = type and=20 single vs. multiple brain metastases. Extracranial disease and baseline=20 performance status were also balanced between the treatment groups. The = primary=20 outcome reported was overall survival. There was no significant = difference=20 between the groups with regard to overall survival. The secondary = outcome of=20 overall response was also similar at approximately 20% in both groups. = This was=20 a combined assessment of brain and extracranial disease response. = Functional=20 performance was not reported. Neurologic cause of death was reported as = 88% in=20 the group with delayed WBRT as opposed to 81% in the group treated with=20 concurrent WBRT and chemotherapy. Adverse events included toxic deaths = in both=20 groups in approximately 8%, and similar instances of myelosuppression, = neuro-=20 and renal toxicity and infection. These were equally distributed in both = groups.=20 </P> <P class=3D"">As a randomized trial of 171 patients, this study provides = class I=20 evidence for the similarity in outcome in the treatment of brain = metastases from=20 NSCLC with chemotherapy with concurrent vs. delayed WBRT. The initial = response=20 rates reported are similar with chemotherapy with or without concurrent = WBRT,=20 but overall survival is not significantly different. This study does not = address=20 the role of concurrent vs. delayed chemotherapy, but rather concurrent = vs.=20 delayed WBRT <I>with</I> chemotherapy, and remains the one and only = study to=20 have attempted to answer the question, without any confirmatory trials.=20 </P></DIV> <DIV class=3D""><A name=3DSec11></A> <HR> <DIV class=3Dheading2>Chemotherapy first followed by WBRT vs. WBRT first = followed=20 by Chemotherapy</DIV> <P class=3D"">Lee et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>]=20 published a randomized trial in 2008 testing the use of systemic = chemotherapy=20 first followed by WBRT vs. WBRT first followed by systemic chemotherapy = for the=20 treatment of advanced NSCLC with synchronous brain metastases. They = treated 25=20 patients with gemicitabine and vinorelbine (up to 6 cycles) used prior = to WBRT=20 and 23 treated with upfront WBRT followed by the same chemotherapy. No=20 WBRT-alone group was included. Patients had histologically verified = NSCLC and=20 clinically silent brain metastasis, not amenable to resection. Patients = were=20 18=9675 years of age, with an ECOG performance status of 0=962, = measurable=20 disease in both intracranial and extracranial sites, and adequate renal, = hepatic=20 and marrow function. The dose of gemcitabine was = 900 mg/m<SUP>2</SUP> on=20 day 1, and vinorelbine was 25 mg/m<SUP>2</SUP> on days 1 and 8, = every=20 3 weeks, with a maximum of 6 cycles or disease progression. WBRT = was=20 administered as 30 Gy in 10 fractions of 3 Gy given over = 2 weeks.=20 In the WBRT-first arm, chemotherapy was initiated after at least a = 2 week=20 rest period. </P> <P class=3D"">In the primary chemotherapy arm, all patients received = WBRT after=20 systemic disease progression or 6 cycles, and no patient had progressive = neurologic symptoms or signs by the time WBRT was started. In the = WBRT-first=20 arm, four patients deteriorated or died prior to receiving chemotherapy. = There=20 was no difference in overall response rates between the two arms (39 vs. = 28%,=20 WBRT first vs. chemo first); intracranial response was closely related = to=20 extracranial response (k =3D 0.82). With a median follow-up of = 40 months, there was no difference in progression-free survival = (PFS) or=20 overall survival. Of note, this study was conducted in Korea, and the = proportion=20 of adenocarcinoma histology was 23/25 in the primary chemotherapy arm, = and 17/23=20 in the WBRT first arm. Quality of life (QOL) parameters were evaluated = in 33=20 patients using the European Organisation for Research and Treatment of = Cancer=20 (EORTC) questionnaires C30 and L13. Global health status was = significantly=20 impaired at baseline, but equally so in both arms. After WBRT, global = health=20 status was found to be significantly impaired, with a decreased mean = score of 48=20 from 65. In the chemotherapy-first arm, cognitive function became more = impaired=20 as chemotherapy proceeded, whereas in the WBRT-first arm, cognitive = function=20 declined for a short period after WBRT, but improved slightly, = thereafter. Grade=20 3 or 4 neutropenia occurred more frequently in the WBRT-first arm (79 = vs. 40%,=20 <I>P</I> =3D 0.014). Other toxicities were comparable. </P> <P class=3D"">As a randomized trial of 48 patients, this study provides = class I=20 evidence for the similarity in outcome in the treatment of brain = metastases from=20 NSCLC with either chemotherapy with delayed WBRT or WBRT followed by=20 chemotherapy, with the caveat that all patients were asymptomatic at = study=20 entry, and patient ethnicity may also need to be factored in, given the = known=20 variability in clinical behavior and response between Caucasian and = Far-Eastern=20 patients. </P></DIV> <DIV class=3D""><A name=3DSec12></A> <HR> <DIV class=3Dheading2>Conclusions and discussion</DIV> <P class=3D"">The role of chemotherapy in the management of brain = metastases has=20 been explored in a very limited number of controlled comparative trials, = and=20 therefore the class of evidence and hence the level of recommendations = have=20 limited applicability. Further, it has to be acknowledged that these=20 recommendations do not apply to the exquisitely chemosensitive tumors, = such as=20 germinomas metastatic to the brain. Additionally, these studies have = been=20 conducted mostly in patients with NSCLC and extrapolating to other = histologic=20 types would be considered inadequately supported by the data. Further=20 confounding the conclusions is the recognition that some of these = patients were=20 pre-treated with chemotherapy, whereas others were chemotherapy-naive, = and the=20 differences in outcomes might reflect prior exposure to systemic = therapy, which=20 has essentially been inadequately accounted for in most of these trials. = Primary=20 endpoints also varied between the trials, with some studies unable to = reach a=20 statistically significant conclusion with regard to a primary endpoint, = such as=20 overall survival, while reporting significant differences in other = secondary=20 endpoints, such as tumor response rates. The variability in these = endpoints=20 contributes to the difficulty in making definitive treatment decisions, = but the=20 caveats are presented so that clinicians can make informed, = individualized=20 clinical decisions for their patients. Lastly, the inclusion in some = trials of=20 only asymptomatic patients also warrants consideration, because results = from=20 such trials cannot be extrapolated to symptomatic patients. </P> <DIV class=3DPara> <DIV class=3D"">Major conclusions that emerge from these studies = include:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>The lack of clear and robust survival benefit with the addition = of=20 chemotherapy to WBRT.</TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>Enhanced response rates, specifically in NSCLC with the addition = of=20 chemotherapy to WBRT.</TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>In terms of secondary endpoints such as time to neurologic=20 progression, steroid dose, etc., the data and results are mixed = and do not=20 permit robust conclusions. </TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>In at least one trial, time to progression was improved by the=20 addition of WBRT to chemotherapy as compared to chemotherapy = alone;=20 however, the evidence to corroborate this study is sparse. = </TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>A single trial provides evidence that outcome is similar whether = WBRT=20 is delivered upfront with chemotherapy or delayed by up to 2 = cycles, but=20 the data remains too limited to support definitive recommendations = for the=20 delay of radiation therapy, especially given the lack of any known = survival advantage with chemotherapy. </TD></TR> <TR vAlign=3Dtop> <TD>6. </TD> <TD>Similarly, the sequencing question (does it matter if = chemotherapy=20 precedes WBRT or vice versa?) has been inadequately addressed and = the data=20 are too sparse to make definitive conclusions.=20 </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec13></A> <HR> <DIV class=3Dheading2>Key issues for future investigation</DIV> <P class=3D"">Although many targeted agents hold some promise in the = management of=20 metastatic disease to the brain, controlled comparative trials are just=20 beginning to be conducted, and the data are not sufficiently mature to = be=20 included in this analysis. This remains a major future area of = investigation.=20 </P> <P class=3D"">Neurocognitive function remains poorly addressed in the = majority of=20 these trials and clearly should be accounted for in future trials. </P> <P class=3D""><I>The following is a list of major ongoing or recently = closed=20 randomized trials pertaining to the use of chemotherapy that evaluate = treatment=20 comparisons addressed by this guideline paper for the management of = newly=20 diagnosed brain metastases:</I> </P> <P class=3D"">1. <I>Temozolomide for Treatment of Brain Metastases From = Non-Small=20 Cell Lung Cancer (Study P03247AM3) (COMPLETED)</I> </P> <P class=3D""><I>Official title</I> A Randomized, Open-Label Phase 2 = Study of=20 Temozolomide Added to Whole Brain Radiation Therapy Versus Whole Brain = Radiation=20 Therapy Alone for the Treatment of Brain Metastasis From Non-Small Cell = Lung=20 Cancer </P> <P class=3D""><I>Status</I> Completed </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00076856 </P> <P class=3D""><I>Principal Investigator</I> Not provided </P> <P class=3D""><I>Location</I> Not provided </P> <P class=3D""><I>Sponsors and Collaborators</I> Schering-Plough </P> <P class=3D"">2. <I>Study of Temozolomide in the Treatment of Brain = Metastasis=20 From Non-Small-Cell Lung Cancer (Study P02143) (COMPLETED)</I> </P> <P class=3D""><I>Official title</I> A Phase II Study of Temozolomide = (SCH 52365)=20 in Subjects With Brain Metastasis From Non-Small-Cell Lung Cancer </P> <P class=3D""><I>Status</I> Completed </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00034697 </P> <P class=3D""><I>Principal Investigator</I> Not provided </P> <P class=3D""><I>Location</I> Not provided </P> <P class=3D""><I>Sponsors and Collaborators</I> Schering-Plough </P> <P class=3D"">3. <I>Safety and Tolerability of Low-Dose Temozolomide = During Whole=20 Brain Radiation in Patients With Cerebral Metastases From Non-Small-Cell = Lung=20 Cancer (Study P04071) (TERMINATED)</I> </P> <P class=3D""><I>Official title</I> Randomized Phase II Study: = Temozolomide (TMZ)=20 Concomitant to Radiotherapy Followed by Sequential TMZ in Advanced NSCLC = Patients With CNS Metastasis Versus Radiotherapy Alone </P> <P class=3D""><I>Status</I> Terminated (Phase II) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00266812 </P> <P class=3D""><I>Principal Investigator</I> Not provided </P> <P class=3D""><I>Location</I> Not provided </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Schering-Plough</P> <P class=3D"">AESCA Pharma GmbH</P> <P class=3D"">4. <I>Radiation Therapy With or Without Temozolomide in = Treating=20 Patients With Non-Small Cell Lung Cancer That is Metastatic to the = Brain</I>=20 </P> <P class=3D""><I>Official title</I> A Phase II Study Of Temozolomide = (SCH 52365)=20 In Subjects With Brain Metastasis From Nonsmall Cell Lung Cancer </P> <P class=3D""><I>Status</I> Active, not recruiting (Phase II) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00030836 </P> <P class=3D""><I>Principal Investigator</I> Lauren E. Abrey, MD, = Memorial=20 Sloan-Kettering Cancer Center </P> <P class=3D""><I>Location</I> United States </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Memorial Sloan-Kettering Cancer Center</P> <P class=3D"">National Cancer Institute (NCI)</P> <P class=3D"">5. <I>Temozolomide With or Without Radiation Therapy to = the Brain in=20 Treating Patients With Stage IV Melanoma That Is Metastatic to the = Brain</I>=20 </P> <P class=3D""><I>Official title</I> Temozolomide Versus=20 Temozolomide + Whole Brain Radiation In Stage IV Melanoma = Patients=20 With Asymptomatic Brain Metastases </P> <P class=3D""><I>Status</I> Active, not recruiting (Phase III) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00020839 </P> <P class=3D""><I>Principal Investigator</I> Juergen C. Becker, MD, PhD=20 Universitaets-Hautklinik Wuerzburg </P> <P class=3D""><I>Location</I> Europe (33 locations) </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">European Organization for Research and Treatment of = Cancer</P> <P class=3D"">6. <I>Radiation Therapy Combined With Either Gefitinib or=20 Temozolomide in Treating Patients With Non-Small Cell Lung Cancer and = Brain=20 Metastases</I> </P> <P class=3D""><I>Official title</I> Whole Brain Radiotherapy in = Combination With=20 Gefitinib (Iressa) or Temozolomide (Temodal) for Brain Metastases From = Non-Small=20 Lung Cancer (NSCLC) A Randomized Phase II Trial </P> <P class=3D""><I>Status</I> Recruiting (Phase II) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00238251 </P> <P class=3D""><I>Principal Investigators</I> </P> <P class=3D"">Study Chair: Gianfranco Pesce, MD Oncology Institute of = Southern=20 Switzerland</P> <P class=3D"">Investigator: Roger Stupp, MD Centre Hospitalier = Universitaire=20 Vaudois</P> <P class=3D""><I>Location</I> Switzerland </P> <P class=3D""><I>Sponsors and Collaborators</I> Swiss Group for Clinical = Cancer=20 Research </P> <P class=3D"">7. <I>Radiation Therapy and Stereotactic Radiosurgery With = or=20 Without Temozolomide or Erlotinib in Treating Patients With Brain = Metastases=20 Secondary to Non-Small Cell Lung Cancer</I> </P> <P class=3D""><I>Official title</I> A Phase III Trial Comparing Whole = Brain=20 Radiation And Stereotactic Radiosurgery Alone Versus With Temozolomide = Or=20 Erlotinib In Patients With Non-Small Cell Lung Cancer And 1-3 Brain = Metastases=20 </P> <P class=3D""><I>Status</I> Recruiting (Phase III) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00096265 </P> <P class=3D""><I>Principal Investigators</I> </P> <P class=3D"">Paul Sperduto, MD, MAPP Park Nicollet Cancer Center</P> <P class=3D"">Minesh P. Mehta, MD University of Wisconsin, Madison</P> <P class=3D"">H. I. Robins, MD, PhD University of Wisconsin, Madison</P> <P class=3D""><I>Location</I> United States and Canada (56 locations) = </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Radiation Therapy Oncology Group</P> <P class=3D"">National Cancer Institute (NCI)</P> <P class=3D"">8. <I>Comparison Study of WBRT and SRS Alone Versus With=20 Temozolomide or Erlotinib in Patients With Brain Metastases of NSCLC</I> = </P> <P class=3D""><I>Official title</I> A Phase III Trial Comparing Whole = Brain=20 Radiation (WBRT) and Stereotactic Radiosurgery (SRS) Alone Versus With=20 Temozolomide or Erlotinib in Patients With Non-Small Cell Lung Cancer = and 1-3=20 Brain Metastases </P> <P class=3D""><I>Status</I> Recruiting (Phase III) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00268684 </P> <P class=3D""><I>Principal Investigator</I> Felix Bokstein, M.D. = Tel-Aviv Sourasky=20 Medical Center </P> <P class=3D""><I>Location</I> Israel </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Tel-Aviv Sourasky Medical Center</P> <P class=3D"">RTOG</P></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgement </SPAN><SPAN = class=3D"">We=20 would like to acknowledge the contributions of the McMaster = Evidence-based=20 Practice Center (EPC), Dr. Parminder Raina, (Director). Dr. Lina = Santaguida=20 (Co-Associate Director, Senior Scientist) led the EPC staff, which was=20 responsible for managing the systematic review process, searching for = and=20 retrieving, reviewing, data abstraction of all articles, preparation of = the=20 tables and the formatting and editing of the final manuscripts.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclaimer=20 of liability</SPAN> The information in these guidelines = reflects the=20 current state of knowledge at the time of completion. The presentations = are=20 designed to provide an accurate review of the subject matter covered. = These=20 guidelines are disseminated with the understanding that the = recommendations by=20 the authors and consultants who have collaborated in their development = are not=20 meant to replace the individualized care and treatment advice from a = patient=92s=20 physician(s). If medical advice or assistance is required, the services = of a=20 competent physician should be sought. The proposals contained in these=20 guidelines may not be suitable for use in all circumstances. The choice = to=20 implement any particular recommendation contained in these guidelines = must be=20 made by a managing physician in light of the situation in each = particular=20 patient and on the basis of existing resources. </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN=20 style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclosures</SPAN> =20 All panel members provided full disclosure of conflicts of interest, if = any,=20 prior to establishing the recommendations contained within these = guidelines.=20 </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN> This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </DIV></DIV></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Gavrilovic IT, Posner JB (2005) Brain = metastases:=20 epidemiology and pathophysiology. 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From: Subject: 10.1007/s11060-009-0062-7 Date: Fri, 25 Dec 2009 04:52:42 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CA851E.17982340" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CA851E.17982340 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/m42x58l615326720/fulltext.html 10.1007/s11060-009-0062-7</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/s11060-009-0062-7</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of chemotherapy in = the management=20 of newly diagnosed brain metastases: a systematic review and = evidence-based=20 clinical practice guideline </DIV> <P class=3DAuthorGroup>Minesh P. Mehta<SUP>1</SUP>,=20 Nina A. Paleologos<SUP>2</SUP>, = Tom Mikkelsen<SUP>3</SUP>,=20 Paula D. Robinson<SUP>4</SUP>, = Mario Ammirati<SUP>5</SUP>,=20 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 Laurie E. Gaspar<SUP>10</SUP>, = Douglas Kondziolka<SUP>11</SUP>,=20 Mark E. Linskey<SUP>12</SUP>, = Jay S. Loeffler<SUP>13</SUP>,=20 Michael McDermott<SUP>14</SUP>, = Jeffrey J. Olson<SUP>15</SUP>,=20 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/m42x58l615326720/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/m42x58l615326720/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 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=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 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=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 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=3DAff11></A>(11) </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=3DAff12></A>(12) </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=3DAff13></A>(13) </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=3DAff14></A>(14) </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=3DAff15></A>(15) </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=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, Hermelin = Brain=20 Tumor Center, Henry Ford Health System, 2799 West Grand Blvd, = K-11,=20 Detroit, MI 48202, USA</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor18></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/m42x58l615326720/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:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>7 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>4 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A = name=3DASec1></A>Target=20 population </SPAN>This recommendation applies to adults with = newly=20 diagnosed brain metastases; however, the recommendation below does not = apply to=20 the exquisitely chemosensitive tumors, such as germinomas metastatic to = the=20 brain. </DIV></DIV> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec2></A>Recommendation </SPAN> <B>Should patients = with brain=20 metastases receive chemotherapy in addition to whole brain radiotherapy=20 (WBRT)?</B>=20 <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Level 1</I></B> Routine use of chemotherapy = following WBRT=20 for brain metastases has not been shown to increase survival and is not=20 recommended. Four class I studies examined the role of carboplatin,=20 chloroethylnitrosoureas, tegafur and temozolomide, and all resulted in = no=20 survival benefit. Two caveats are provided in order to allow the = treating=20 physician to individualize decision-making: First, the majority of the = data are=20 limited to non small cell lung (NSCLC) and breast cancer; therefore, in = other=20 tumor histologies, the possibility of clinical benefit cannot be = absolutely=20 ruled out. Second, the addition of chemotherapy to WBRT improved = response rates=20 in some, but not all trials; response rate was not the primary endpoint = in most=20 of these trials and end-point assessment was non-centralized, = non-blinded, and=20 post-hoc. Enrollment in chemotherapy-related clinical trials is = encouraged.=20 </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Chemotherapy - Whole brain radiation=20 therapy - Targeted agents - Systematic=20 review - Practice guideline </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Rationale</DIV> <P class=3D"">Brain metastases are a common complication of systemic = cancer,=20 occurring in 20=9640% of patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR1">1</A></CITE>].=20 The primary therapeutic approach for disseminated systemic disease = remains=20 chemotherapy, and therefore, one might expect this to be a logical = choice for=20 brain metastases as well. However, several issues have limited the = application=20 of chemotherapy in this context. One concern involves the ability of=20 chemotherapeutic agents to cross the blood=96brain barrier (BBB). Many=20 chemotherapeutic agents are relatively excluded from the brain, and ones = that do=20 penetrate, may do so in insufficient concentrations. Although there is = relative=20 breakdown of the BBB in and around a metastatic lesion in the brain, = some=20 studies have demonstrated that there is still only very limited drug=20 concentration within the lesion. Recent findings suggest that efflux = pumps may=20 play a major role in this phenomenon [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR2">2</A></CITE>].=20 Some animal studies have shown that if metastatic tumors enhance = strongly on=20 computed tomography (CT) or magnetic resonance imaging (MRI), that the=20 blood=96brain barrier (BBB) is sufficiently impaired to allow entry of=20 chemotherapeutic drugs. Newer agents which cross the BBB have and are = being=20 developed as well. New molecular based therapies directed against growth = factor=20 receptors and other protein kinases are being investigated, however = their large=20 size also raises concerns about penetrability. There is also the = long-standing=20 observation that intracranial response rates to chemotherapy are = typically lower=20 than in the extracranial compartment, and a common hypothesis for this = finding=20 is that patients are pre-exposed to cytotoxic therapies, and it is the=20 chemoresistant clones that metastasize to the brain. However, data in = newly=20 diagnosed, previously untreated patients with small cell lung cancer = (SCLC)=20 suggest that intracranial response rates remain significantly lower than = extracranial response rates, thereby suggesting that chemoresistant = clones alone=20 do not necessarily explain this dichotomy [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR3">3</A></CITE>].=20 Some types of metastatic brain tumors may respond to chemotherapy to = some=20 degree, including breast cancer, germ cell cancer, and ovarian cancer in = addition to SCLC. </P> <DIV class=3DPara> <DIV class=3D"">The use of chemotherapy for brain metastases has been = explored in=20 four primary contexts:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>WBRT vs. WBRT plus chemotherapy</TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>Chemotherapy vs. chemotherapy plus WBRT</TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>Chemotherapy plus concurrent WBRT vs. chemotherapy plus delayed=20 WBRT</TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>Chemotherapy first, followed by WBRT vs. WBRT first, followed by = chemotherapy</TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <P class=3D"">To answer the above question and its subparts, a = comprehensive=20 systematic literature review was performed.</P> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane = Database=20 of Abstracts of Reviews of Effects. A broad search strategy using a = combination=20 of subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR4">4</A></CITE>]=20 Reference lists of included studies were also reviewed. </P> <DIV class=3DPara> <DIV class=3D"">For inclusion in this analysis, the following criteria = had to be=20 met:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English with a publication date of 1990 = forward.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Patients with newly diagnosed brain metastases.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Fully published peer-reviewed primary comparative studies (all=20 comparative study designs for primary data collection included; = e.g., RCT,=20 non-randomized trials, cohort studies or case=96control studies). = </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Any comparative studies evaluating chemotherapy alone or in=20 combination with other treatment modalities for the treatment of = newly=20 diagnosed brain metastases. </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Number of study participants with newly diagnosed brain = metastases ≥5=20 per study arm for at least two of the study arms.</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Baseline information on study participants is provided by = treatment=20 group in studies evaluating interventions exclusively in patients = with=20 newly diagnosed brain metastases. For studies with mixed = populations=20 (i.e., includes participants with conditions other than newly = diagnosed=20 brain metastases), baseline information is provided for the = intervention=20 sub-groups of participants with newly diagnosed brain metastases.=20 </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec4></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/m42x58l615326720/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR6">6</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=3DSec5></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper for this guideline = series.=20 </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">The literature search resulted in the identification of = 16,966=20 citations of which 16,936 were eliminated at abstract review as not = having=20 relevance to the specific question. The remaining 30 studies were = subject to=20 full text screening, and 20 were excluded, seven because they lacked = baseline=20 patient data by treatment group, 10 because they lacked baseline patient = subset=20 data by treatment group, two because there was no treatment comparison = of=20 interest, and one because it was not a comparative study. Ten eligible = studies=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>]=20 were therefore fully reviewed and form the basis of this report (see=20 Table <A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#Tab1">1</A>;=20 Fig. <A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#Fig1">1</A>).<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Summary = of primary=20 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""><I>WBRT vs. WBRT + chemotherapy</I> = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Guerrieri (2004) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 21) </P> <P class=3D"">G2: WBRT + Carboplatin = (<I>n</I> =3D 21)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 4.4 months</P> <P class=3D"">G2: 3.7 months (survival curves: log-rank;=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response in brain: (Of evaluable pts)</P> <P class=3D"">G1: OR 10% (of 11 pts assessed)</P> <P class=3D"">G2: OR 29% (of 16 pts assessed) = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Ushio (1991) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR8">8</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 25) </P> <P class=3D"">G2: WBRT + Chloroethylnitrosoureas=20 (<I>n</I> =3D 34) </P> <P class=3D"">G3:=20 WBRT + Chloroethylnirosoureas + Tegafur=20 (<I>n</I> =3D 29) </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from lung cancer</P></TD> <TD align=3Dleft> <P class=3D"">G1: 27 weeks</P> <P class=3D"">G2: 29 weeks</P> <P class=3D"">G3: 30.5 weeks (survival curves: Wilcoxon;=20 <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 36% (CR 4/14, PR 1/14)</P> <P class=3D"">G2: OR 69% (CR 11/16, PR 0/16)</P> <P class=3D"">G3: OR 74% (CR 12/19, PR 2/19)</P> <P class=3D"">G1 vs. G2 (<I>P</I> =3D NS) </P> <P class=3D"">G2 vs. G3 (<I>P</I> =3D NS) </P> <P class=3D"">G1 vs. G3 (<I>P</I> < 0.05) </P></TD> <TD align=3Dleft> <P class=3D"">NR</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Antonadou (2002) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR9">9</A></CITE>]=20 </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"">Pts with 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 (survival curves: log-rank;=20 <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"">Verger (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR10">10</A></CITE>]=20 </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"">Pts with BM</P></TD> <TD align=3Dleft> <P class=3D"">G1: 3.1 months</P> <P class=3D"">G2: 4.5 months (survival curves: log-rank;=20 <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"">Kim (2005) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: WBRT (<I>n</I> =3D 32) </P> <P class=3D"">G2: WBRT + platinum-based chemotherapy=20 (<I>n</I> =3D 31) </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM at diagnosis of NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 19.0 weeks</P> <P class=3D"">G2: 58.1 weeks (survival curves: test not = specified:=20 <I>P</I> < 0.001) </P></TD> <TD align=3Dleft> <P class=3D"">No comparison between groups</P></TD> <TD align=3Dleft> <P class=3D"">No comparison between groups</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D""><I>Chemotherapy vs. = chemotherapy + WBRT</I>=20 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Mornex (2003) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR12">12</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: 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"">Pts with BM from melanoma</P></TD> <TD align=3Dleft> <P class=3D"">G1: 86 days</P> <P class=3D"">G2: 105 days (survival curves: log-rank;=20 <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 (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"">Postmus (2000) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR13">13</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: Teniposide (<I>n</I> =3D 60) </P> <P class=3D"">G2: Teniposide + WBRT = (<I>n</I> =3D 60)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from SCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 3.2 months</P> <P class=3D"">G2: 3.5 months (survival curves: log-rank;=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (by ITT)</P> <P class=3D"">G1: OR 22% (CR 5/60, PR 8/60)</P> <P class=3D"">G2: OR 57% (CR 18/60, PR 16/60)=20 (<I>P</I> < 0.001) </P> <P class=3D"">Response rate outside the brain:</P> <P class=3D"">G1: OR 20% (CR 3/60, PR 9/60)</P> <P class=3D"">G2: OR 33% (CR 6/60, PR 14/60) = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median time to progression in brain: NR</P> <P class=3D"">Significant difference in favor of G2 (BM = progression-free=20 curves: log-rank; <I>P</I> =3D 0.005) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Moscetti (2006) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR14">14</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">Retrospective cohort study</P> <P class=3D"">Evidence class II</P></TD> <TD align=3Dleft> <P class=3D"">G1: Platinum-based chemotherapy = (<I>n</I> =3D 110)=20 </P> <P class=3D"">G2: WBRT + chemotherapy = (<I>n</I> =3D 46)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM at diagnosis of NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 10 months</P> <P class=3D"">G2: 14 months (survival curves: test not = specified;=20 <I>P</I> =3D 0.07; NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (OR by ITT)</P> <P class=3D"">G1: OR 27.3% (CR 15/107, PR 15/107)</P> <P class=3D"">G2: OR 34.8% (CR 2/46, PR 14/46) = (<I>P</I> =3D NS)=20 </P> <P class=3D"">Extra-cranial response rate:</P> <P class=3D"">G1: OR 34.5% (CR 0/107, PR 38/107)</P> <P class=3D"">G2: OR 41.3% (CR 0/46, PR 19/46) = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Median progression-free survival:</P> <P class=3D"">G1: 6 months</P> <P class=3D"">G2: 6 months (Progression-free curves: test not = specified; <I>P</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D""><I>Chemotherapy + concurrent WBRT vs.=20 chemotherapy + delayed WBRT</I> </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Robinet (1998) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR15">15</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: = Cisplatin + vinorelbine + delayed WBRT=20 (<I>n</I> =3D 86) </P> <P class=3D"">G2: = Cisplatin + vinorelbine + concurrent=20 WBRT (<I>n</I> =3D 85) </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 24 weeks</P> <P class=3D"">G2: 21 weeks (survival curves: log-rank;=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Response rate in brain: (by ITT)</P> <P class=3D"">G1: OR 27% (CR 1/76, PR 22/76)</P> <P class=3D"">G2: OR 33% (CR 7/73, PR 21/73) = (<I>P</I> =3D NS) </P> <P class=3D"">Extra-cranial rate response:</P> <P class=3D"">G1: OR 35% (CR 2/76, PR 28/76)</P> <P class=3D"">G2: OR 25% (CR 2/73, PR 19/73) = (<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: 13 weeks</P> <P class=3D"">G2: 11 weeks (BM progression-free curves: = log-rank;=20 <I>P</I> =3D NS) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D7> <P class=3D""><I>WBRT + delayed chemotherapy vs.=20 chemotherapy + delayed WBRT</I> </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lee (2008) [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>]=20 </P></TD> <TD align=3Dleft> <P class=3D"">RCT</P> <P class=3D"">Evidence class I</P></TD> <TD align=3Dleft> <P class=3D"">G1: Chemotherapy followed by WBRT = (<I>n</I> =3D 25)=20 </P> <P class=3D"">G2: WBRT followed by chemotherapy = (<I>n</I> =3D 23)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Pts with BM from NSCLC</P></TD> <TD align=3Dleft> <P class=3D"">G1: 9.1 months</P> <P class=3D"">G2: 9.9 months (survival curves; log-rank:=20 <I>P</I> =3D NS) </P></TD> <TD align=3Dleft> <P class=3D"">Overall response in brain:</P> <P class=3D"">G1: PR 7/25, SD 10/25, PD 8/25</P> <P class=3D"">G2: PR 9/23, SD 4/23, PD 6/23 = (<I>P</I> =3D NS)=20 </P></TD> <TD align=3Dleft> <P class=3D"">Progression free survival:</P> <P class=3D"">G1: 3.6 months</P> <P class=3D"">G2: 4.4 months (<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>G1</I> = group 1,=20 <I>G2</I> group 2, <I>G3</I> group 3, <I>G4</I> group 4, <I>ITT</I>=20 intention-to-treat, <I>NR</I> not reported, <I>NS</I> not significant,=20 <I>NSCLC</I> non-small cell lung cancer, <I>OR</I> objective response, = <I>PD</I>=20 progressive disease, <I>PR</I> partial response, <I>Pts</I> patients, = <I>RCT</I>=20 randomized control trial, <I>SCLC</I> small-cell lung cancer, <I>SD</I> = stable=20 disease, <I>TMZ</I> temozolomide; <I>WBRT</I> whole-brain radiation = therapy=20 </DIV></DIV></DIV> <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_62_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/m42x58l615326720/MediaObjects/= 11060_2009_62_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV class=3D"">These 10 studies were assigned to the four sub-questions = above as=20 follows:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD> </TD> <TD>WBRT vs. WBRT + chemotherapy: 5 studies [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>].=20 </TD></TR> <TR vAlign=3Dtop> <TD> </TD> <TD>Chemotherapy vs. chemotherapy + WBRT: 3 studies = [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR17">17</A></CITE>].=20 </TD></TR> <TR vAlign=3Dtop> <TD> </TD> <TD>Chemotherapy + concurrent WBRT vs.=20 chemotherapy + delayed WBRT: 1 study [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR15">15</A></CITE>].=20 </TD></TR> <TR vAlign=3Dtop> <TD> </TD> <TD>Chemotherapy first, followed by WBRT vs. WBRT first, followed by = chemotherapy: 1 study [<CITE><A=20 = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>].=20 </TD></TR></TBODY></TABLE></DIV></DIV> <P class=3D"">Clearly, the role of chemotherapy in the management of = brain=20 metastases has been explored in a very limited number of controlled = comparative=20 trials, and therefore the class of evidence and hence the level of=20 recommendations have limited applicability. In addition, outcome = parameters vary=20 between the studies, further complicating direct comparisons; = nonetheless, these=20 studies do provide important information regarding the endpoints of = survival,=20 tumor response to therapy, and time to progression for specific clinical = scenarios. Further, we must also acknowledge that these recommendations = do not=20 apply to the exquisitely chemosensitive tumors, such as germinomas = metastatic to=20 the brain. Finally, although many targeted agents hold some promise in = the=20 management of metastatic disease to the brain, controlled comparative = trials are=20 just beginning to be conducted, and the data are not sufficiently mature = to be=20 included in this analysis. Refer to Table <A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#Tab1">1</A>=20 for details of the included studies. </P></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>WBRT vs. WBRT plus chemotherapy</DIV> <P class=3D"">Five studies [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>]=20 met the inclusion criteria for this sub-question. Four of five studies = provide=20 class I evidence (two are phase III randomized trials, and two are = randomized=20 phase II trials) and the fifth is a retrospective cohort study, = providing, at=20 best, class II evidence. </P> <P class=3D"">In 2004 Guerrieri et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR7">7</A></CITE>]=20 published a multi-institutional, randomized controlled trial (RCT) of = palliative=20 radiation with concomitant carboplatin for patients with brain = metastases from=20 NSCLC, with overall survival as the primary endpoint. Patients with=20 histologically or cytologically proven NSCLC, with ≥1 brain = metastases=20 identified by CT or MRI, deemed either inoperable or who refused = surgery, with a=20 WHO performance status of 0, 1 or 2, and who had adequate laboratory = parameters=20 were included. Prior chemotherapy or brain radiotherapy were exclusion = criteria.=20 Patients were stratified by institution. Forty-two patients were = randomized to=20 two groups, G1: WBRT (<I>n</I> =3D 21) G2: = WBRT + Carboplatin=20 (<I>n</I> =3D 21). The radiotherapy dose was 20 Gy in 5 = fractions=20 in both arms and the Carboplatin dose was 70 mg/m<SUP>2</SUP> = IV/day =D7=20 5 days. The detailed demographic breakdown is presented in the = tabular=20 summary. Patients were well-balanced between the two arms by age, = gender,=20 histology, and number of brain lesions; the status of extra-cranial = disease was=20 not reported. There was a mismatch in terms of WHO performance status = between=20 the two groups; there were 33% vs. 67% PS 1 patients in G1 vs. G2, and = 52% vs.=20 19% PS 2 patients in G1 vs. G2. Additionally, in G1, 24% of patients had = a=20 neurologic function status of 3, compared to 5% in G2. Median follow-up = was not=20 reported. The degree of steroid usage in each of the two groups was not=20 reported. The trial was terminated early due to low patient accrual, = thus=20 limiting the ability to draw statistically significant conclusions. </P> <P class=3D"">The median survival was comparable, 4.4 vs. = 3.7 months for G1=20 vs. G2, which was statistically not significant. Overall response was = reported=20 in a subset of patients. Of 11 assessed patients in G1, the OR was 10%, = compared=20 to 29% in 16 patients in G2, which was statistically not significantly=20 different; however, when patients were compared in terms of WHO = performance=20 status compared to pre-treatment, 14% in G1 were worse, and 57% in G2 = were=20 worse; similarly, in terms of neurological function status compared to=20 pre-treatment, 10% were worse in G1, compared to 38% in G2. Although WHO = performance and neurologic function deterioration were more common in = G2, there=20 were no significant differences in gastrointestinal or hematological = toxicities=20 between the groups. </P> <P class=3D"">This trial, with incomplete accrual, failed to meet the = primary=20 objective of demonstrating improved survival with the addition of = carboplatin to=20 WBRT in NSCLC patients with brain metastases. While designed as a class = I study,=20 the aforementioned concerns regarding this trial may further limit its = impact=20 when making treatment recommendations, as no statistically significant=20 differences in survival were noted between the groups. However, the = study does=20 appear to support the use of chemotherapy when secondary endpoints such = as=20 response rate are analyzed. </P> <P class=3D"">The second major RCT, also designed as a class I study, = was reported=20 by Ushio et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR8">8</A></CITE>]=20 in 1991. Patients with a diagnosis of brain metastases from lung cancer = with the=20 primary lesion and/or systemic lesions relatively well controlled, and a = projected survival of >4 months, were enrolled. Previous = chemotherapy=20 with any of the drugs used in this study was an exclusion factor. = Patients were=20 randomized to three groups: G1: WBRT alone (<I>n</I> =3D 25), = G2:=20 WBRT + Chloroethylnitrosoureas (either methyl-CCNU or ACNU)=20 (<I>n</I> =3D 34), G3:=20 WBRT + Tegafur + Chloroethylnitrosoureas=20 (<I>n</I> =3D 29). In all three groups, surgery was permitted = prior to=20 WBRT, if the lesions could be removed without neurologic deficits. The = WBRT dose=20 was 40 Gy in 1.5=962 Gy fractions; the methyl-CCNU dose was=20 100=96120 mg/m<SUP>2</SUP> orally every 6=968 weeks (at = midpoint in the=20 study, methyl-CCNU became unavailable and was replaced with ACNU=20 80=96100 mg/m<SUP>2</SUP> IV every 6=968 weeks) and the = Tegafur dose was=20 300 mg/m<SUP>2</SUP>/day given orally. Patients were well balanced = in all=20 three groups by gender, age, histology, and number of brain metastases. = The=20 status of extra-cranial disease, the degree of corticosteroid use, and = baseline=20 functional performance score was not reported, and median follow-up of = patients=20 was not available. </P> <P class=3D"">The primary endpoint was tumor control, but median = survival was also=20 analyzed. There was no statistically significant difference in survival = between=20 the three arms (27, 29, and 30.5 weeks for G1, G2 and G3 = respectively).=20 Intracranial response analysis revealed an overall response rate of 36, = 69, and=20 74% for groups 1=963, respectively. When the response rate for group 1 = was=20 statistically compared to that of group 3, it reached statistical = significance,=20 with a <I>P</I> < 0.05 (overall response rate: 36 vs. 74%; = the=20 comparable complete response rates for the two groups were four of 14 = patients=20 vs. 12 of 19 patients). Functional performance outcome was not reported = nor was=20 the time to intracranial recurrence/progression. The causes of death = were=20 ascertained, and the rate of neurologic death was 3/25 in G1, 0/32 in G2 = and=20 4/28 in G3. Adverse events were not reported in detail in the study; = however two=20 patients were thought to have died from the effects of chemotherapy (one = from=20 pancytopenia and one from cardiac failure). </P> <P class=3D"">In summary, this RCT of 88 patients did not show a = survival=20 improvement with the addition of chemotherapy, but showed a = statistically=20 significant improvement in response rates, especially the rates of = complete=20 response, with the addition of Tegafur and a nitrosourea to WBRT in = patients=20 with NSCLC. </P> <P class=3D"">In 2002, Antonadou et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR9">9</A></CITE>]=20 reported on a phase II RCT in which patients with brain metastases were=20 randomized to WBRT alone or WBRT plus temozolomide. Adult patients aged = 18 or=20 older, with brain metastases from histologically proven cancer of the = lung,=20 breast, or unknown primary, with a performance status ≤2, life = expectancy=20 ≥3 months, and adequate hematologic, renal, hepatic function, = were=20 included. Exclusion factors were previous chemotherapy or radiotherapy = for brain=20 metastases, or any uncontrollable, life-threatening systemic disease, or = pregnant or lactating women. Patients (<I>n</I> =3D 23) in = group 1=20 received 40 Gy of WBRT in 20 fractions of 2 Gy each. In group = 2,=20 (<I>n</I> =3D 25) patients received the same dose of WBRT with = 75 mg/m<SUP>2</SUP>/day of temozolomide orally during WBRT and = continued=20 temozolomide therapy (200 mg/m<SUP>2</SUP>/day for 5 days = every=20 28 days for an additional 6 cycles after WBRT. The median follow-up = time=20 was 4 months. The groups were well-balanced with respect to gender, = age,=20 baseline performance status, neurologic functional level, and tumor = type, with=20 65% of patients having NSCLC, as well as number of brain metastases and = presence=20 of extracranial disease. </P> <P class=3D"">The primary study endpoints were radiologic response and = neurologic=20 symptom evaluation. Survival was also analyzed. The median survival was = 7 vs.=20 8.6 months for G1 vs. G2 (not statistically significant). The = overall=20 response rate was 67% vs. 96% for G1 vs.G2, with a = <I>P</I> =3D 0.017=20 which was statistically significant. The time to recurrence or = progression of=20 disease in the brain, and also the cause of death were not reported. = There was=20 neurologic improvement in the group receiving temozolomide, and fewer = patients=20 required corticosteroids after treatment in the temozolomide group = compared with=20 radiotherapy alone. The temozolomide was generally well tolerated with = some=20 toxicities statistically more common in that group, including nausea, = and=20 vomiting. Hematologic toxicity was reversible. </P> <P class=3D"">In summary, this RCT of 48 patients did not show a = survival=20 improvement with the addition of temozolomide chemotherapy, but showed a = statistically significant improvement in response rates and an = improvement in=20 neurologic function with the addition of temozolomide to WBRT, which = constitutes=20 class I evidence. We are aware of a subsequent larger randomized trial = performed=20 by the same group, but this has never been published in manuscript form = and is=20 therefore not available as a peer-reviewed literature item. </P> <P class=3D"">In 2003, Verger et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR10">10</A></CITE>]=20 reported on a phase II RCT in patients with brain metastases randomized = to WBRT=20 alone or WBRT plus temozolomide. Adult patients aged 18 or older, with = brain=20 metastases from histologically proven cancer, unsuitable for surgery or = SRS,=20 with a Karnofsky performance score (KPS) ≥50, and adequate = hematologic, renal,=20 and hepatic function, were included. Exclusion factors included previous = chemotherapy within the previous 3 weeks, prior cranial = radiotherapy,=20 leptomeningeal involvement, intratumoral hemorrhage, and clinical or = psychiatric=20 conditions that would interfere with completion or required evaluations. = </P> <P class=3D"">Stratification variables included age, KPS and type of = primary=20 tumor. Patients (<I>n</I> =3D 41) in G1 received 30 Gy = WBRT in 10=20 fractions of 3 Gy. In G2, 41 patients received the same dose of = WBRT with=20 75 mg/m<SUP>2</SUP>/day of temozolomide orally during WBRT and = continued=20 temozolomide therapy (150=96200 mg/m<SUP>2</SUP>/day for = 5 days every=20 28 days for an additional 2 cycles after WBRT.) The median = follow-up time=20 was not reported. The groups were well-balanced with respect to gender, = age,=20 baseline performance status, tumor type (with 53 and 49% of patients = having=20 NSCLC), number of brain metastases and presence of extracranial disease. = </P> <P class=3D"">Unlike in the other studies mentioned above, the primary = outcome in=20 this trial was an analysis of neurologic toxicity. Radiologic response = and=20 progression free survival were also analyzed secondarily. The trial was = stopped=20 prematurely due to low patient accrual. The median survival was 3.1 vs.=20 4.5 months for G1 vs. G2 and was not statistically significant. The = overall=20 response at day 30 was 32% for both G1 and G2. At 90 days, the = radiologic=20 response could only be assessed in 35 patients and was similar in the = two=20 groups. Freedom from intracranial progression at 90 days was 54 vs. = 72%=20 (<I>P</I> =3D 0.03) in favor of the WBRT plus temozolomide = group.=20 Functional performance change was not reported. There was a = statistically=20 significant difference in cause of death between the two groups, with = neurologic=20 death occurring in 69% in G1 compared to 41% in G2 = (<I>P</I> =3D 0.029)=20 again favoring the WBRT plus temozolomide group. No acute neurologic = toxicity=20 developed in the WBRT plus temozolomide arm and temozolomide did not = interfere=20 with delivery of WBRT. </P> <P class=3D"">In summary, this prematurely terminated RCT of 82 = patients, which=20 was designed as a class I study, did not show either a survival = improvement with=20 the addition of temozolomide chemotherapy, or statistically significant=20 improvement in response rates, with the addition of temozolomide to = WBRT.=20 Although insufficient to support a level 1 recommendation, the evidence = in this=20 study did show an improvement with the addition of chemotherapy in the = secondary=20 endpoints of intracranial progression and neurologic death. </P> <P class=3D"">Finally, in 2005, Kim et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR11">11</A></CITE>]=20 published a retrospective cohort study which included NSCLC patients = with=20 synchronous brain metastases who received WBRT for intracranial lesions = found=20 during evaluation of neurologic symptoms. The exclusion criteria were = patients=20 who did not receive WBRT, leptomeningeal carcinomatosis, Eastern = Cooperative=20 Oncology Group (ECOG) performance status of grade 3 or 4, surgical = resection or=20 radiotherapy for thoracic lesions, or open surgical removal of = intracranial=20 metastatic lesions. The interventions included G1: WBRT=20 (<I>n</I> =3D 32) and G2: WBRT + platinum-based = chemotherapy=20 (<I>n</I> =3D 31). The WBRT dose was 30 to 40 Gy, and = several=20 platinum doublets were employed. </P> <P class=3D"">The median follow-up was not reported. The groups were = well balanced=20 in terms of gender, age, tumor type (100% NSCLC), number of brain = metastases,=20 presence of extracranial disease, and baseline performance score. The = primary=20 outcome was not specified, but there was a marked difference in median = survival,=20 G1: 19.0 weeks vs. G2: 58.1 weeks = (<I>P</I> < 0.001). No=20 data were presented regarding tumor control, time to intracranial = recurrence, or=20 cause of death. The neurologic response was not significantly different = between=20 the two groups. </P> <P class=3D"">In summary, this non-randomized cohort study of 63 = patients showed a=20 survival improvement with the addition of various platinum-based doublet = chemotherapies in addition to WBRT. This constitutes class II evidence. = There=20 was no improvement in secondary endpoints. </P></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Chemotherapy vs. chemotherapy plus WBRT</DIV> <P class=3D"">In 2003, Mornex et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR12">12</A></CITE>]=20 published results of a prospective randomized phase III trial of = fotemustine=20 plus WBRT (<I>n</I> =3D 37) versus fotemustine alone=20 (<I>n</I> =3D 39) in patients with cerebral metastases from = malignant=20 melanoma. The main objectives were objective response and time to = cerebral=20 progression. Patients with histologically confirmed malignant melanoma = with at=20 least one non-resectable metastasis and who fit other parameters were = included.=20 Patients were required to have received no chemotherapy in the prior=20 4 weeks, no previous nitrosourea-based chemotherapy and no previous = cerebral radiotherapy. Both arms were well balanced with respect to the = number=20 of cerebral metastases, extent of visceral disease and age. Patients in = the=20 fotemustine alone arm had worse baseline performance status (ECOG 2=963 = 54%=20 compared to 30% in the fotemustine plus WBRT group) and had been treated = with=20 more chemoimmunotherapy (59 versus 32% respectively). Additionally, the = median=20 time interval between the primary diagnosis and the onset of brain = metastases=20 was different between the two groups (550 days for the fotemustine = alone=20 group and 1131 days for the fotemustine + WBRT group). = The dose=20 of WBRT was 37.5 Gy in 15 fractions over 3 weeks. Fotemustine = was=20 given intravenously at 100 mg/m<SUP>2</SUP> on days 1, 8 and 15, = followed=20 by a 5 week rest period and then every 3 weeks in = non-progressing=20 patients. Although the fotemustine alone patients had worse prognostic = factors,=20 there was no difference in cerebral response or control or in overall = survival=20 (86 days in the fotemustine group vs. 105 days in the combined = treatment group). There was a statistically significant difference in = time to=20 cerebral progression favoring the WBRT + fotemustine group=20 (<I>P</I> =3D 0.028) with that group having a median time to = objective=20 cerebral progression of 56 days compared to 49 days in the=20 chemotherapy alone group. This constitutes class I evidence. </P> <P class=3D"">A phase III randomized study comparing teniposide (G1) = versus=20 teniposide with WBRT (G2) in patients with brain metastases from SCLC = was=20 reported by Postmus et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR13">13</A></CITE>]=20 in 2000. Their stated goal was to evaluate the role of WBRT in SCLC = patients=20 with brain metastases. The primary end point was survival. Teniposide = was=20 administered intravenously at 120 mg/m<SUP>2</SUP> on days 1, 3, = and 5=20 every 3 weeks up to a maximum of 12 courses or until disease = progression=20 either inside or outside the brain. WBRT, dosed at 30 Gy in 10 = fractions=20 over 2 weeks, had to be started within 3 weeks of the start of = treatment with teniposide. Dexamethasone dosing parameters were = outlined. Of the=20 134 patients randomized, 120 were eligible (60 in each group). The = groups were=20 well matched for age, ECOG performance status, neurologic function and = number of=20 brain metastases. Although the response rate in the combined modality = group (G2)=20 was significantly higher (57%) than in the teniposide alone group (G1) = (22%),=20 this did not result in a prolongation of overall survival, thought to be = due to=20 progression of disease outside the brain (3.2 months in G1 and=20 3.5 months in G2). Time to progression in the brain was assessed by = CT scan=20 rather than MRI in this European study and was significantly longer in = the=20 combined modality group. This RCT constitutes class I evidence. </P> <P class=3D"">In a retrospective cohort study, Moscetti et al. [<CITE><A = href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR14">14</A></CITE>]=20 analyzed 110 patients (G1) with newly diagnosed NSCLC with brain = metastases who=20 had received up-front platinum-based chemotherapy and 46 patients who = had=20 received WBRT followed by chemotherapy (G2). The authors sought to = analyze the=20 process by which six oncologic centers guided the pattern of care. In = this=20 survey of unselected patients, choice of treatment appeared guided by = presence=20 of neurologic symptoms from the brain metastases. The response rate in = the brain=20 was 27.3% in G1 and 34.8% in G2 with no significant difference in median = time to=20 progression in the brain (6 months in both groups). With regard to = the=20 first treatment option, the median survival was 10 months for G1 = and=20 14 months for G2. While this study does show that some patients = with brain=20 metastases from NSCLC will respond initially to platinum-based = chemotherapy,=20 there are too many variables in the patient cohorts and reasons for = treatment=20 choice to derive any meaningful data for recommendation. This = retrospective=20 study constitutes class II evidence. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Chemotherapy with concomitant WBRT vs. = chemotherapy with=20 delayed WBRT</DIV> <P class=3D"">Robinet et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR15">15</A></CITE>]=20 published a randomized trial in 1998 evaluating the use of systemic = chemotherapy=20 for the treatment of inoperable brain metastases from NSCLC with early = WBRT=20 versus WBRT delayed until progression. They treated 85 patients with = cisplatin=20 and vinorelbine used concurrently with WBRT and 86 treated with the same = chemotherapy, but with WBRT delayed for at least 2 cycles. No WBRT-alone = group=20 was included. Patients had histologically verified NSCLC and at least = one brain=20 metastasis >10 mm in diameter. Patients had an acceptable = performance=20 status and good end-organ function. Patients were treated with cisplatin = 100 mg/m<SUP>2</SUP> on day 1, vinorelbine 30 mg/m<SUP>2</SUP> = on days=20 1, 8, 15 and 22, with cycles repeated every 4 weeks. In one group,=20 chemotherapy was started concurrent with WBRT, administered as = 30 Gy in 10=20 fractions of 3 Gy given over 2 weeks. In the other group, = radiation=20 was deferred. </P> <P class=3D"">Median follow-up was not reported, but 171 patients were = accrued and=20 the two treatment groups were balanced with regard to age, sex, tumor = type and=20 single vs. multiple brain metastases. Extracranial disease and baseline=20 performance status were also balanced between the treatment groups. The = primary=20 outcome reported was overall survival. There was no significant = difference=20 between the groups with regard to overall survival. The secondary = outcome of=20 overall response was also similar at approximately 20% in both groups. = This was=20 a combined assessment of brain and extracranial disease response. = Functional=20 performance was not reported. Neurologic cause of death was reported as = 88% in=20 the group with delayed WBRT as opposed to 81% in the group treated with=20 concurrent WBRT and chemotherapy. Adverse events included toxic deaths = in both=20 groups in approximately 8%, and similar instances of myelosuppression, = neuro-=20 and renal toxicity and infection. These were equally distributed in both = groups.=20 </P> <P class=3D"">As a randomized trial of 171 patients, this study provides = class I=20 evidence for the similarity in outcome in the treatment of brain = metastases from=20 NSCLC with chemotherapy with concurrent vs. delayed WBRT. The initial = response=20 rates reported are similar with chemotherapy with or without concurrent = WBRT,=20 but overall survival is not significantly different. This study does not = address=20 the role of concurrent vs. delayed chemotherapy, but rather concurrent = vs.=20 delayed WBRT <I>with</I> chemotherapy, and remains the one and only = study to=20 have attempted to answer the question, without any confirmatory trials.=20 </P></DIV> <DIV class=3D""><A name=3DSec11></A> <HR> <DIV class=3Dheading2>Chemotherapy first followed by WBRT vs. WBRT first = followed=20 by Chemotherapy</DIV> <P class=3D"">Lee et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/m42x58l615326720/fulltext.htm= l#CR16">16</A></CITE>]=20 published a randomized trial in 2008 testing the use of systemic = chemotherapy=20 first followed by WBRT vs. WBRT first followed by systemic chemotherapy = for the=20 treatment of advanced NSCLC with synchronous brain metastases. They = treated 25=20 patients with gemicitabine and vinorelbine (up to 6 cycles) used prior = to WBRT=20 and 23 treated with upfront WBRT followed by the same chemotherapy. No=20 WBRT-alone group was included. Patients had histologically verified = NSCLC and=20 clinically silent brain metastasis, not amenable to resection. Patients = were=20 18=9675 years of age, with an ECOG performance status of 0=962, = measurable=20 disease in both intracranial and extracranial sites, and adequate renal, = hepatic=20 and marrow function. The dose of gemcitabine was = 900 mg/m<SUP>2</SUP> on=20 day 1, and vinorelbine was 25 mg/m<SUP>2</SUP> on days 1 and 8, = every=20 3 weeks, with a maximum of 6 cycles or disease progression. WBRT = was=20 administered as 30 Gy in 10 fractions of 3 Gy given over = 2 weeks.=20 In the WBRT-first arm, chemotherapy was initiated after at least a = 2 week=20 rest period. </P> <P class=3D"">In the primary chemotherapy arm, all patients received = WBRT after=20 systemic disease progression or 6 cycles, and no patient had progressive = neurologic symptoms or signs by the time WBRT was started. In the = WBRT-first=20 arm, four patients deteriorated or died prior to receiving chemotherapy. = There=20 was no difference in overall response rates between the two arms (39 vs. = 28%,=20 WBRT first vs. chemo first); intracranial response was closely related = to=20 extracranial response (k =3D 0.82). With a median follow-up of = 40 months, there was no difference in progression-free survival = (PFS) or=20 overall survival. Of note, this study was conducted in Korea, and the = proportion=20 of adenocarcinoma histology was 23/25 in the primary chemotherapy arm, = and 17/23=20 in the WBRT first arm. Quality of life (QOL) parameters were evaluated = in 33=20 patients using the European Organisation for Research and Treatment of = Cancer=20 (EORTC) questionnaires C30 and L13. Global health status was = significantly=20 impaired at baseline, but equally so in both arms. After WBRT, global = health=20 status was found to be significantly impaired, with a decreased mean = score of 48=20 from 65. In the chemotherapy-first arm, cognitive function became more = impaired=20 as chemotherapy proceeded, whereas in the WBRT-first arm, cognitive = function=20 declined for a short period after WBRT, but improved slightly, = thereafter. Grade=20 3 or 4 neutropenia occurred more frequently in the WBRT-first arm (79 = vs. 40%,=20 <I>P</I> =3D 0.014). Other toxicities were comparable. </P> <P class=3D"">As a randomized trial of 48 patients, this study provides = class I=20 evidence for the similarity in outcome in the treatment of brain = metastases from=20 NSCLC with either chemotherapy with delayed WBRT or WBRT followed by=20 chemotherapy, with the caveat that all patients were asymptomatic at = study=20 entry, and patient ethnicity may also need to be factored in, given the = known=20 variability in clinical behavior and response between Caucasian and = Far-Eastern=20 patients. </P></DIV> <DIV class=3D""><A name=3DSec12></A> <HR> <DIV class=3Dheading2>Conclusions and discussion</DIV> <P class=3D"">The role of chemotherapy in the management of brain = metastases has=20 been explored in a very limited number of controlled comparative trials, = and=20 therefore the class of evidence and hence the level of recommendations = have=20 limited applicability. Further, it has to be acknowledged that these=20 recommendations do not apply to the exquisitely chemosensitive tumors, = such as=20 germinomas metastatic to the brain. Additionally, these studies have = been=20 conducted mostly in patients with NSCLC and extrapolating to other = histologic=20 types would be considered inadequately supported by the data. Further=20 confounding the conclusions is the recognition that some of these = patients were=20 pre-treated with chemotherapy, whereas others were chemotherapy-naive, = and the=20 differences in outcomes might reflect prior exposure to systemic = therapy, which=20 has essentially been inadequately accounted for in most of these trials. = Primary=20 endpoints also varied between the trials, with some studies unable to = reach a=20 statistically significant conclusion with regard to a primary endpoint, = such as=20 overall survival, while reporting significant differences in other = secondary=20 endpoints, such as tumor response rates. The variability in these = endpoints=20 contributes to the difficulty in making definitive treatment decisions, = but the=20 caveats are presented so that clinicians can make informed, = individualized=20 clinical decisions for their patients. Lastly, the inclusion in some = trials of=20 only asymptomatic patients also warrants consideration, because results = from=20 such trials cannot be extrapolated to symptomatic patients. </P> <DIV class=3DPara> <DIV class=3D"">Major conclusions that emerge from these studies = include:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>The lack of clear and robust survival benefit with the addition = of=20 chemotherapy to WBRT.</TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>Enhanced response rates, specifically in NSCLC with the addition = of=20 chemotherapy to WBRT.</TD></TR> <TR vAlign=3Dtop> <TD>3. </TD> <TD>In terms of secondary endpoints such as time to neurologic=20 progression, steroid dose, etc., the data and results are mixed = and do not=20 permit robust conclusions. </TD></TR> <TR vAlign=3Dtop> <TD>4. </TD> <TD>In at least one trial, time to progression was improved by the=20 addition of WBRT to chemotherapy as compared to chemotherapy = alone;=20 however, the evidence to corroborate this study is sparse. = </TD></TR> <TR vAlign=3Dtop> <TD>5. </TD> <TD>A single trial provides evidence that outcome is similar whether = WBRT=20 is delivered upfront with chemotherapy or delayed by up to 2 = cycles, but=20 the data remains too limited to support definitive recommendations = for the=20 delay of radiation therapy, especially given the lack of any known = survival advantage with chemotherapy. </TD></TR> <TR vAlign=3Dtop> <TD>6. </TD> <TD>Similarly, the sequencing question (does it matter if = chemotherapy=20 precedes WBRT or vice versa?) has been inadequately addressed and = the data=20 are too sparse to make definitive conclusions.=20 </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec13></A> <HR> <DIV class=3Dheading2>Key issues for future investigation</DIV> <P class=3D"">Although many targeted agents hold some promise in the = management of=20 metastatic disease to the brain, controlled comparative trials are just=20 beginning to be conducted, and the data are not sufficiently mature to = be=20 included in this analysis. This remains a major future area of = investigation.=20 </P> <P class=3D"">Neurocognitive function remains poorly addressed in the = majority of=20 these trials and clearly should be accounted for in future trials. </P> <P class=3D""><I>The following is a list of major ongoing or recently = closed=20 randomized trials pertaining to the use of chemotherapy that evaluate = treatment=20 comparisons addressed by this guideline paper for the management of = newly=20 diagnosed brain metastases:</I> </P> <P class=3D"">1. <I>Temozolomide for Treatment of Brain Metastases From = Non-Small=20 Cell Lung Cancer (Study P03247AM3) (COMPLETED)</I> </P> <P class=3D""><I>Official title</I> A Randomized, Open-Label Phase 2 = Study of=20 Temozolomide Added to Whole Brain Radiation Therapy Versus Whole Brain = Radiation=20 Therapy Alone for the Treatment of Brain Metastasis From Non-Small Cell = Lung=20 Cancer </P> <P class=3D""><I>Status</I> Completed </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00076856 </P> <P class=3D""><I>Principal Investigator</I> Not provided </P> <P class=3D""><I>Location</I> Not provided </P> <P class=3D""><I>Sponsors and Collaborators</I> Schering-Plough </P> <P class=3D"">2. <I>Study of Temozolomide in the Treatment of Brain = Metastasis=20 From Non-Small-Cell Lung Cancer (Study P02143) (COMPLETED)</I> </P> <P class=3D""><I>Official title</I> A Phase II Study of Temozolomide = (SCH 52365)=20 in Subjects With Brain Metastasis From Non-Small-Cell Lung Cancer </P> <P class=3D""><I>Status</I> Completed </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00034697 </P> <P class=3D""><I>Principal Investigator</I> Not provided </P> <P class=3D""><I>Location</I> Not provided </P> <P class=3D""><I>Sponsors and Collaborators</I> Schering-Plough </P> <P class=3D"">3. <I>Safety and Tolerability of Low-Dose Temozolomide = During Whole=20 Brain Radiation in Patients With Cerebral Metastases From Non-Small-Cell = Lung=20 Cancer (Study P04071) (TERMINATED)</I> </P> <P class=3D""><I>Official title</I> Randomized Phase II Study: = Temozolomide (TMZ)=20 Concomitant to Radiotherapy Followed by Sequential TMZ in Advanced NSCLC = Patients With CNS Metastasis Versus Radiotherapy Alone </P> <P class=3D""><I>Status</I> Terminated (Phase II) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00266812 </P> <P class=3D""><I>Principal Investigator</I> Not provided </P> <P class=3D""><I>Location</I> Not provided </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Schering-Plough</P> <P class=3D"">AESCA Pharma GmbH</P> <P class=3D"">4. <I>Radiation Therapy With or Without Temozolomide in = Treating=20 Patients With Non-Small Cell Lung Cancer That is Metastatic to the = Brain</I>=20 </P> <P class=3D""><I>Official title</I> A Phase II Study Of Temozolomide = (SCH 52365)=20 In Subjects With Brain Metastasis From Nonsmall Cell Lung Cancer </P> <P class=3D""><I>Status</I> Active, not recruiting (Phase II) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00030836 </P> <P class=3D""><I>Principal Investigator</I> Lauren E. Abrey, MD, = Memorial=20 Sloan-Kettering Cancer Center </P> <P class=3D""><I>Location</I> United States </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Memorial Sloan-Kettering Cancer Center</P> <P class=3D"">National Cancer Institute (NCI)</P> <P class=3D"">5. <I>Temozolomide With or Without Radiation Therapy to = the Brain in=20 Treating Patients With Stage IV Melanoma That Is Metastatic to the = Brain</I>=20 </P> <P class=3D""><I>Official title</I> Temozolomide Versus=20 Temozolomide + Whole Brain Radiation In Stage IV Melanoma = Patients=20 With Asymptomatic Brain Metastases </P> <P class=3D""><I>Status</I> Active, not recruiting (Phase III) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00020839 </P> <P class=3D""><I>Principal Investigator</I> Juergen C. Becker, MD, PhD=20 Universitaets-Hautklinik Wuerzburg </P> <P class=3D""><I>Location</I> Europe (33 locations) </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">European Organization for Research and Treatment of = Cancer</P> <P class=3D"">6. <I>Radiation Therapy Combined With Either Gefitinib or=20 Temozolomide in Treating Patients With Non-Small Cell Lung Cancer and = Brain=20 Metastases</I> </P> <P class=3D""><I>Official title</I> Whole Brain Radiotherapy in = Combination With=20 Gefitinib (Iressa) or Temozolomide (Temodal) for Brain Metastases From = Non-Small=20 Lung Cancer (NSCLC) A Randomized Phase II Trial </P> <P class=3D""><I>Status</I> Recruiting (Phase II) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00238251 </P> <P class=3D""><I>Principal Investigators</I> </P> <P class=3D"">Study Chair: Gianfranco Pesce, MD Oncology Institute of = Southern=20 Switzerland</P> <P class=3D"">Investigator: Roger Stupp, MD Centre Hospitalier = Universitaire=20 Vaudois</P> <P class=3D""><I>Location</I> Switzerland </P> <P class=3D""><I>Sponsors and Collaborators</I> Swiss Group for Clinical = Cancer=20 Research </P> <P class=3D"">7. <I>Radiation Therapy and Stereotactic Radiosurgery With = or=20 Without Temozolomide or Erlotinib in Treating Patients With Brain = Metastases=20 Secondary to Non-Small Cell Lung Cancer</I> </P> <P class=3D""><I>Official title</I> A Phase III Trial Comparing Whole = Brain=20 Radiation And Stereotactic Radiosurgery Alone Versus With Temozolomide = Or=20 Erlotinib In Patients With Non-Small Cell Lung Cancer And 1-3 Brain = Metastases=20 </P> <P class=3D""><I>Status</I> Recruiting (Phase III) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00096265 </P> <P class=3D""><I>Principal Investigators</I> </P> <P class=3D"">Paul Sperduto, MD, MAPP Park Nicollet Cancer Center</P> <P class=3D"">Minesh P. Mehta, MD University of Wisconsin, Madison</P> <P class=3D"">H. I. Robins, MD, PhD University of Wisconsin, Madison</P> <P class=3D""><I>Location</I> United States and Canada (56 locations) = </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Radiation Therapy Oncology Group</P> <P class=3D"">National Cancer Institute (NCI)</P> <P class=3D"">8. <I>Comparison Study of WBRT and SRS Alone Versus With=20 Temozolomide or Erlotinib in Patients With Brain Metastases of NSCLC</I> = </P> <P class=3D""><I>Official title</I> A Phase III Trial Comparing Whole = Brain=20 Radiation (WBRT) and Stereotactic Radiosurgery (SRS) Alone Versus With=20 Temozolomide or Erlotinib in Patients With Non-Small Cell Lung Cancer = and 1-3=20 Brain Metastases </P> <P class=3D""><I>Status</I> Recruiting (Phase III) </P> <P class=3D""><I>Clinicaltrials.gov Identifier</I> NCT00268684 </P> <P class=3D""><I>Principal Investigator</I> Felix Bokstein, M.D. = Tel-Aviv Sourasky=20 Medical Center </P> <P class=3D""><I>Location</I> Israel </P> <P class=3D""><I>Sponsors and Collaborators</I> </P> <P class=3D"">Tel-Aviv Sourasky Medical Center</P> <P class=3D"">RTOG</P></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgement </SPAN><SPAN = class=3D"">We=20 would like to acknowledge the contributions of the McMaster = Evidence-based=20 Practice Center (EPC), Dr. Parminder Raina, (Director). Dr. Lina = Santaguida=20 (Co-Associate Director, Senior Scientist) led the EPC staff, which was=20 responsible for managing the systematic review process, searching for = and=20 retrieving, reviewing, data abstraction of all articles, preparation of = the=20 tables and the formatting and editing of the final manuscripts.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclaimer=20 of liability</SPAN> The information in these guidelines = reflects the=20 current state of knowledge at the time of completion. The presentations = are=20 designed to provide an accurate review of the subject matter covered. = These=20 guidelines are disseminated with the understanding that the = recommendations by=20 the authors and consultants who have collaborated in their development = are not=20 meant to replace the individualized care and treatment advice from a = patient=92s=20 physician(s). If medical advice or assistance is required, the services = of a=20 competent physician should be sought. The proposals contained in these=20 guidelines may not be suitable for use in all circumstances. The choice = to=20 implement any particular recommendation contained in these guidelines = must be=20 made by a managing physician in light of the situation in each = particular=20 patient and on the basis of existing resources. </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN=20 style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclosures</SPAN> =20 All panel members provided full disclosure of conflicts of interest, if = any,=20 prior to establishing the recommendations contained within these = guidelines.=20 </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN> This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </DIV></DIV></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Gavrilovic IT, Posner JB (2005) Brain = metastases:=20 epidemiology and pathophysiology. 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