From: Subject: 10.1007/s11060-009-0056-5 Date: Fri, 18 Dec 2009 18:56:40 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0011_01CA8013.D5596520" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0011_01CA8013.D5596520 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/v69317g735r2381m/fulltext.html 10.1007/s11060-009-0056-5</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/s11060-009-0056-5</TD></TR></TBODY></TABLE><!--Begin = Abstract--> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of prophylactic = anticonvulsants=20 in the management of brain metastases: a systematic review and = evidence-based=20 clinical practice guideline </DIV> <P class=3DAuthorGroup>Tom Mikkelsen<SUP>1</SUP>,=20 Nina A. Paleologos<SUP>2</SUP>,=20 Paula D. Robinson<SUP>3</SUP>, = Mario Ammirati<SUP>4</SUP>,=20 David W. Andrews<SUP>5</SUP>, = Anthony L. Asher<SUP>6</SUP>,=20 Stuart H. Burri<SUP>7</SUP>, = Charles S. Cobbs<SUP>8</SUP>,=20 Laurie E. Gaspar<SUP>9</SUP>, = Douglas Kondziolka<SUP>10</SUP>,=20 Mark E. Linskey<SUP>11</SUP>, = Jay S. Loeffler<SUP>12</SUP>,=20 Michael McDermott<SUP>13</SUP>, = Minesh P. Mehta<SUP>14</SUP>,=20 Jeffrey J. Olson<SUP>15</SUP>, = Roy A. Patchell<SUP>16</SUP>,=20 Timothy C. Ryken<SUP>17</SUP> and=20 Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/v69317g735r2381m/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 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=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>McMaster University Evidence-Based = Practice=20 Centre, Ontario, Canada</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of 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=3DAff5></A>(5) </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=3DAff6></A>(6) </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=3DAff7></A>(7) </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=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosciences, = California=20 Pacific Medical Center, San Francisco, CA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology, = University=20 of Colorado-Denver, Denver, CO, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurological Surgery, = University=20 of Pittsburgh Medical Center, Pittsburgh, PA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff11></A>(11) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California-Irvine Medical Center, Orange, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff12></A>(12) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Radiation Oncology,=20 Massachusetts General Hospital, Boston, MA, = USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff13></A>(13) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, University = of=20 California San Francisco, San Francisco, CA,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff14></A>(14) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Human Oncology, = University of=20 Wisconsin School of Public Health and Medicine, Madison, WI,=20 USA</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff15></A>(15) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of 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>Hermelin Brain Tumor Center, = Department of=20 Neurosurgery, 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/v69317g735r2381m/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>7 September 2009  <STRONG>Accepted:=20 </STRONG>8 November 2009  <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B>   </SPAN>Do prophylactic=20 anticonvulsants decrease the risk of seizure in patients with metastatic = brain=20 tumors compared with no treatment?=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">These recommendations apply to adults with solid brain = metastases=20 who have not experienced a seizure due to their metastatic brain = disease.=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendation</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> For adults with brain metastases who have = not=20 experienced a seizure due to their metastatic brain disease, routine=20 prophylactic use of anticonvulsants is not recommended. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Only a single underpowered randomized controlled trial = (RCT),=20 which did not detect a difference in seizure occurrence, provides = evidence for=20 decision-making purposes. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords  </SPAN>Brain=20 metastases - Anticonvulsant - Prophylaxis - = ;Seizures - 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 approximately 20=9640% of patients. Since an intracranial = mass lesion=20 may predispose patients to seizure, the question has arisen as to = whether=20 prophylactic use of anticonvulsants may prevent seizures in this = population.=20 Previously published guidelines on this topic have included patients = with both=20 primary and secondary brain tumors [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR2">2</A></CITE>].=20 </P> <P class=3D"">The objective of this guideline paper is to specifically = address the=20 role of anticonvulsant prophylaxis in adults with solid metastases to = the brain.=20 The rationale for this is that intracranial metastases from systemic = cancer tend=20 to be spherical and more contained when compared to primary brain tumors = which=20 are more infiltrative in nature. Given this difference in typical growth = patterns, it is conventionally thought that brain metastases may be less = likely=20 to induce seizures than primary tumors. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, Cochrane = Database of=20 Abstracts of Reviews of Effects. A broad search strategy using a = combination of=20 subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR3">3</A></CITE>]=20 Reference lists of included studies were also reviewed. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Eligibility criteria</DIV> <DIV class=3DPara> <DIV class=3D"">For inclusion in this systematic review the following = criteria=20 needed to be 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 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>Study comparisons include the=20 following:</TD></TR></TBODY></TABLE></DIV></DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>anticonvulsant prophylaxis vs. = none</TD></TR></TBODY></TABLE></DIV></DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN>  </TD> <TD>Number of study participants with brain = metastases ≥ 5 per=20 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 brain metastases. For studies with mixed populations (i.e., = includes=20 participants with conditions other than brain metastases), = baseline=20 information is provided for the intervention sub-groups of = participants=20 with brain metastases. = </TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Study selection and quality assessment</DIV> <P class=3D"">Two independent reviewers evaluated citations using a = priori=20 criteria for relevance and documented decisions in standardized forms. = Cases of=20 disagreement were resolved by a third reviewer. The same methodology was = used=20 for full text screening of potentially relevant papers. Studies which = met the=20 eligibility criteria were data extracted by one reviewer and the = extracted=20 information was checked by a second reviewer. The PEDro scale [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR5">5</A></CITE>]=20 was used to rate the quality of randomized trials. The quality of = comparative=20 studies using non-randomized designs was evaluated using eight items = selected=20 and modified from existing scales. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Evidence classification and recommendation = levels</DIV> <P class=3D"">Both the quality of the evidence and the strength of the=20 recommendations were graded according to the American Association of=20 Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) = criteria.=20 These criteria are provided in the methodology paper for this guideline = series.=20 </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">The literature search resulted in the identification of = 16,966=20 citations of which 16,962 were eliminated at abstract review as not = having=20 relevance to the specific question. The remaining four studies were = subject to=20 full text screening, three of which were excluded because they lacked = baseline=20 patient data for brain metastases sub-group. Only one study [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR6">6</A></CITE>]=20 met the eligibility criteria and forms the basis of this report (see=20 Fig. <A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#Fig1">1</A>).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_56_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/v69317g735r2381m/MediaObjects/= 11060_2009_56_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"">Clearly, the role of anticonvulsant use specifically in = the=20 management of brain metastases has been explored in a very limited = number of=20 controlled comparative trials, and therefore the class of evidence and = hence the=20 recommendations have limited applicability. Table <A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#Tab1">1</A>=20 summarizes the only applicable study, in terms of class of evidence.<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Study = evaluating the=20 role of anticonvulsant use in the management of brain metastases </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft colSpan=3D3> <P class=3D"">First author (year): Forsyth [<CITE><A=20 = href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR6">6</A></CITE>]=20 (2003) </P></TH></TR> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Study characteristics</P></TH> <TH align=3Dleft> <P class=3D"">Study outcomes</P></TH> <TH align=3Dleft> <P class=3D"">Study quality</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Study design: RCT (Data extracted for BM subgroup,=20 <I>n</I> =3D 60/100) </P> <P class=3D"">[Stratified by primary vs. metastatic brain tumor; = within=20 metastatic group, further stratification by melanoma vs. = non-melanoma=20 primaries] </P> <P class=3D"">Inclusion criteria:</P> <P class=3D""> Pathologically documented brain tumor or = systemic cancer=20 with BM,</P> <P class=3D""> Newly diagnosed (recruited ≤1 month = of brain tumor=20 diagnosis)</P> <P class=3D""> Adequate hepatic, bone marrow and renal = function</P> <P class=3D"">Exclusion criteria:</P> <P class=3D""> Life = expectancy < 4 weeks</P> <P class=3D""> Prior seizures</P> <P class=3D""> Known allergy to anticonvulsants</P> <P class=3D""> Pregnancy, lactation, or ineffective use of=20 contraception</P> <P class=3D""> Ethanol or drug abuse</P> <P class=3D"">Interventions:</P> <P class=3D""> G1: Anticonvulsants (Phenytoin = <I>n</I> =3D 25;=20 Phenobarbital <I>n</I> =3D 1) </P> <P class=3D""> G2: No Anticonvulsants = (<I>n</I> =3D 34) </P> <P class=3D"">Dose:</P> <P class=3D""> G1: Loading dose 15 mg/kg phenytoin in 3 = divided=20 doses, with a standard daily dose of 5 mg/kg p.o.; phenytoin=20 intolerance was replaced with phenobarbital (60 mg p.o. for=20 1 week then 90 mg daily) </P> <P class=3D""> Median follow-up: Not reported by treatment or = sub-group</P> <P class=3D""> Overall follow-up: 5.44 months</P> <P class=3D""># male:</P> <P class=3D""> G1: 18/26 (69%)</P> <P class=3D""> G2: 14/34 (41%)</P> <P class=3D"">Median age (range): Not reported by median</P> <P class=3D""> Mean age:</P> <P class=3D"">  G1: 60.9 years</P> <P class=3D"">  G2: 57.5 years</P> <P class=3D"">Tumor type:</P> <P class=3D""> G1: Lung 18/26, breast 1/26, melanoma 1/26, = other=20 6/26</P> <P class=3D""> G2: Lung 14/34, breast 8/34, melanoma 3/34, = other=20 9/34</P> <P class=3D""># of brain metastases:</P> <P class=3D""> Not reported</P> <P class=3D"">Extra-cranial disease:</P> <P class=3D""> Not reported</P> <P class=3D"">Baseline functional performance: Mean KPS</P> <P class=3D""> G1: 78</P> <P class=3D""> G2: 73.8</P></TD> <TD align=3Dleft> <P class=3D"">Primary outcome: Seizure occurrence 3 months=20 post-randomization</P> <P class=3D"">% seizure-free at 3 months: Not reported for BM = sub-groups</P> <P class=3D"">Seizure-free survival curves for BM sub-groups: = log-rank;=20 <I>P</I> =3D NS </P> <P class=3D"">Anticonvulsant toxicity: Not reported by BM = sub-group</P> <P class=3D"">Study terminated after 100 patients enrolled (60 = with brain=20 metastases and 40 with primary brain tumors):</P> <P class=3D"">The study was stopped because: (1) the observed = seizure rate=20 at 3 months in the no anticonvulsant group was 10% which put = the=20 predicted rate of 20% outside the 95% CI of 0.6 to 19.8% and (2) = mortality=20 prior to 3 months of follow-up, projected to be 15% was = approximately=20 30%. The combination of these two factors indicated that the power = of the=20 study (based on an accrual of 300 pts) to detect a clinically = important=20 difference was reduced to < %. </P></TD> <TD align=3Dleft> <P class=3D"">PEDro scale:</P> <P class=3D"">1. Eligibility criteria specified? YES</P> <P class=3D"">2. Random allocation? YES</P> <P class=3D"">3. Allocation concealed? YES</P> <P class=3D"">4. Groups similar at baseline on most important = prognostic=20 indicators? YES</P> <P class=3D"">5. Subjects blinded to treatment? NO</P> <P class=3D"">6. Blinding of clinicians who administered = treatment? NO</P> <P class=3D"">7. Blinding of assessors who measured at least 1 key = outcome?=20 NO</P> <P class=3D"">8. Measures of at least 1 key outcome from more than = 85%=20 subjects initially allocated to groups? YES</P> <P class=3D"">9. All subjects for whom outcome measures were = available=20 received the treatment or control condition as allocated or data = was=20 analyzed by =93intention to treat=94? YES </P> <P class=3D"">10. Results of between-group statistical comparisons = are=20 reported for at least one key outcome? YES</P> <P class=3D"">11. Study provides both point measures and measures = of=20 variability for at least 1 key outcome? YES</P> <P class=3D"">AANS/CNS evidence classification: Class=20 1</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>Abbreviations</I>: <I>AANS</I> American Association = of=20 Neurological Surgeons, <I>BM</I> brain metastasis, <I>CI</I> Confidence=20 Interval, <I>CNS</I> Congress of Neurological Surgeons, <I>G1</I> group = 1,=20 <I>G2</I> group 2, <I>G3</I> group 3, <I>G4</I> group 4, <I>KPS</I> = Karnofsky=20 performance score, <I>NS</I> not significant, <I>RCT</I> randomized = controlled=20 trial </DIV></DIV></DIV></DIV></DIV> <P class=3D"">This study, by Forsyth et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR6">6</A></CITE>],=20 is an RCT of anticonvulsants versus no anticonvulsants in 100 patients = with=20 newly diagnosed brain tumors (diagnosis <1 month from study = entry).=20 Patients were stratified for primary (<I>n</I> =3D 40) or = metastatic=20 (<I>n</I> =3D 60) pathology. Additional eligibility criteria = were=20 adequate hepatic, bone marrow and renal function. Excluded were patients = with=20 limited life expectancy (<4 weeks), known prior seizures, = anticonvulsant=20 allergy, substance abuse and pregnancy. Of patients with brain = metastasis, 26=20 were treated with anticonvulsants, usually phenytoin = (<I>n</I> =3D 25)=20 or phenobarbital (<I>n</I> =3D 1) using oral loading and = conventional=20 maintenance dosing; 34 patients received no anticonvulsants. The = primary=20 outcome reported was seizure occurrence at 3 months = post-randomization.=20 </P> <P class=3D"">The trial was terminated early because the seizure rate in = the no=20 anticonvulsant arm was only 10%, which put the anticipated seizure rate = of 20%=20 outside the 95% confidence interval. In addition, mortality prior to the = 3-month=20 follow-up was much higher than anticipated (observed 30% vs. projected = 15%). The=20 authors of the trial noted that the combination of these two factors = indicated=20 that the power to detect a clinically important difference in seizure = occurrence=20 between the two groups would be less than 20% based on the planned-for = accrual=20 of 300 patients. </P> <P class=3D"">The only outcome reported specifically for the sub-group = of patients=20 with brain metastases was seizure incidence, and there was no = significant=20 difference between those who received anticonvulsant prophylaxis and = those who=20 did not (log rank test; <I>P</I> =3D 0.90). </P></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Conclusions and discussion</DIV> <P class=3D"">It is very difficult to make recommendations regarding the = role of=20 anticonvulsant prophylaxis in patients with brain metastases based on = sub-group=20 data from one underpowered randomized trial. All of the studies = evaluating=20 prophylactic anticonvulsant use identified by this systematic review = included=20 patients with both primary and secondary tumors. Only one of these = trials=20 stratified by metastases versus primary pathology and presented baseline = data=20 for the brain metastases sub-group and, therefore, met the eligibility = criteria=20 for this systematic review. </P> <P class=3D"">Given the premise that brain metastases are probably less = likely=20 than primary brain tumors to cause seizures, it is noteworthy that = previously=20 published guidelines on the role of anticonvulsants in patients with = brain=20 tumors (either primary or secondary) have recommended against their = prophylactic=20 use [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR2">2</A></CITE>].=20 Although only the single aforementioned study met our search criteria, = the=20 rationale for making a Level 3 recommendation not to use routine = prophylactic=20 anticonvulsants is further explained by the fact that anticonvulsant use = can=20 have significant adverse effects, and by the lack of evidence suggesting = any=20 benefit from the prophylactic use of anticonvulsants for patients with = brain=20 metastases. The key conclusion from these guidelines, then, is that = there is a=20 lack of a clear and robust benefit from the routine prophylactic use of=20 anticonvulsants. </P></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Key issues for future investigation</DIV> <DIV class=3DPara> <DIV class=3D"">Given the ubiquity of anticonvulsant use for = prophylactic and=20 active treatment of seizures associated with metastatic brain disease, = the=20 medical literature contains relatively few detailed reports specifically = addressing their use. Future studies could be planned to allow better = control,=20 recording and analysis of anticonvulsant dosing and response to allow a = more=20 robust analysis of the risk to benefit ratio of various agents. A host = of newer=20 anticonvulsants are now available and in widespread use [<CITE><A=20 href=3D"http://www.springerlink.com/content/v69317g735r2381m/fulltext.htm= l#CR7">7</A></CITE>].=20 These often have a better safety profile than older agents and lower = likelihood=20 for significant drug interactions. Although patients with metastatic = carcinoma=20 may be prone to seizure, prophylactic anticonvulsant use is not = recommended.=20 Once a seizure has occurred, however, anticonvulsants are safe and = effective,=20 especially the newer agents. Unresolved questions which could be the = subject of=20 prospective studies include the prognosis for patients with a single=20 peri-operative seizure versus multiple symptomatic seizures, with = regards to=20 long-term control, adverse effects of therapy and safety.=20 <BLOCKQUOTE> <P class=3D""><I>No ongoing or recently closed clinical trials on the=20 prophylactic use of anticonvulsants for the management of brain = metastases=20 were found that met the eligibility criteria.</I>=20 </P></BLOCKQUOTE></DIV></DIV></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments  </SPAN><SPAN = class=3D"">We=20 would like to acknowledge the contributions of the McMaster = Evidence-based=20 Practice Center (EPC), Dr. Parminder Raina, (Director). Dr. Lina = Santaguida=20 (Co-Associate Director, Senior Scientist) led the EPC staff, which was=20 responsible for managing the systematic review process, searching for = and=20 retrieving, reviewing, data abstraction of all articles, preparation of = the=20 tables and the formatting and editing of the final manuscripts.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclaimer=20 of liability</SPAN>   The information in these guidelines = reflects the=20 current state of knowledge at the time of completion. The presentations = are=20 designed to provide an accurate review of the subject matter covered. = These=20 guidelines are disseminated with the understanding that the = recommendations by=20 the authors and consultants who have collaborated in their development = are not=20 meant to replace the individualized care and treatment advice from a = patient=92s=20 physician(s). If medical advice or assistance is required, the services = of a=20 competent physician should be sought. The proposals contained in these=20 guidelines may not be suitable for use in all circumstances. The choice = to=20 implement any particular recommendation contained in these guidelines = must be=20 made by a managing physician in light of the situation in each = particular=20 patient and on the basis of existing resources. </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN=20 style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Disclosures</SPAN>  =20 All panel members provided full disclosure of conflicts of interest, if = any,=20 prior to establishing the recommendations contained within these = guidelines.=20 </DIV></DIV> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN>   This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </DIV></DIV></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Perry J, Zinman L, Chambers A, Spithoff K, = Lloyd N,=20 Laperriere N (2006) The use of prophylactic anticonvulsants in = patients=20 with brain tumours=97a systematic review. 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