10.1007/s11060-009-0057-4</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.16945" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0057-4</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of steroids in the = management of=20 brain metastases: a systematic review and evidence-based clinical = practice=20 guideline </DIV> <P class=3DAuthorGroup>Timothy C. Ryken<SUP>1</SUP>,=20 Michael McDermott<SUP>2</SUP>, = Paula D. Robinson<SUP>3</SUP>,=20 Mario Ammirati<SUP>4</SUP>, David W. Andrews<SUP>5</SUP>, = Anthony L. Asher<SUP>6</SUP>, = Stuart H. Burri<SUP>7</SUP>,=20 Charles S. Cobbs<SUP>8</SUP>, = Laurie E. Gaspar<SUP>9</SUP>,=20 Douglas Kondziolka<SUP>10</SUP>, = Mark E. Linskey<SUP>11</SUP>,=20 Jay S. Loeffler<SUP>12</SUP>, = Minesh P. Mehta<SUP>13</SUP>,=20 Tom Mikkelsen<SUP>14</SUP>, = Jeffrey J. Olson<SUP>15</SUP>,=20 Nina A. Paleologos<SUP>16</SUP>,=20 Roy A. Patchell<SUP>17</SUP> and=20 Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/n11832031700653r/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, 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=3DAff2></A>(2) </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=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>McMaster University Evidence-Based = Practice=20 Centre, Hamilton, ON, 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 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=3DAff14></A>(14) </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=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, Northshore = University=20 Health System, Evanston, IL, 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 Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, 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/n11832031700653r/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>8 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B> </SPAN>Do steroids improve = neurologic=20 symptoms in patients with metastatic brain tumors compared to no = treatment? If=20 steroids are given, what dose should be used? Comparisons include: (1) = steroid=20 therapy versus none. (2) comparison of different doses of steroid = therapy.=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">These recommendations apply to adults diagnosed with = brain=20 metastases.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Steroid therapy versus no steroid therapy</I></B>=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Asymptomatic brain metastases patients without mass = effect</I>=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Insufficient evidence exists to make a treatment = recommendation=20 for this clinical scenario.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Brain metastases patients with mild symptoms related = to mass=20 effect</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Corticosteroids are recommended to = provide=20 temporary symptomatic relief of symptoms related to increased = intracranial=20 pressure and edema secondary to brain metastases. It is recommended for = patients=20 who are symptomatic from metastatic disease to the brain that a starting = dose of=20 4=968 mg/day of dexamethasone be considered. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Brain metastases patients with moderate to severe = symptoms=20 related to mass effect</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Corticosteroids are recommended to = provide=20 temporary symptomatic relief of symptoms related to increased = intracranial=20 pressure and edema secondary to brain metastases. If patients exhibit = severe=20 symptoms consistent with increased intracranial pressure, it is = recommended that=20 higher doses such as 16 mg/day or more be considered. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Choice of Steroid</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> If corticosteroids are given, = dexamethasone is the=20 best drug choice given the available evidence. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Duration of Corticosteroid Administration</I> = </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Corticosteroids, if given, should be = tapered slowly=20 over a 2 week time period, or longer in symptomatic patients, based = upon an=20 individualized treatment regimen and a full understanding of the = long-term=20 sequelae of corticosteroid therapy. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Given the very limited number of studies (two) which met = the=20 eligibility criteria for the systematic review, these are the only=20 recommendations that can be offered based on this methodology. Please = see =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=94=20 and =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec14">Summary</A>=94=20 section for additional details. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Steroids - Neurologic=20 symptoms - Steroid dosage - 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"">Glucocorticoids have typically been used to assist in = controlling=20 cerebral edema in the early supportive care of the patient with newly = diagnosed=20 metastatic brain disease. Dexamethasone is generally considered the = steroid of=20 choice because of its minimal mineralocorticoid effect and long = half-life,=20 although any other corticosteroid can be effective if given in = equipotent doses.=20 Steroids have been used alone for palliation of symptoms and in = combination with=20 radiotherapy as an initial course of therapy. A review of the available=20 literature indicates that the majority of these patients have been = managed with=20 starting doses of 4=968 mg/day and it has been stated that up to = 75% of=20 patients with brain metastases show marked neurological improvement = within=20 24=9672 h after beginning dexamethasone [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>].=20 However, side effects from chronic dexamethasone administration, = including=20 myopathy, are frequent and contribute to disability. Asymptomatic or = minimally=20 symptomatic patients may benefit little from the routine administration = of=20 steroid therapy and be exposed to these toxicities. Although successful = clinical=20 experience would lead to the conclusion that the role of steroids is = firmly=20 established in the management of brain metastases, even a cursory review = of the=20 literature will demonstrate significant variability in recommendations = and a=20 general lack of well-controlled studies addressing this specific issue. = </P> <DIV class=3DPara> <DIV class=3D"">This systematic review addresses the role of = corticosteroids in=20 the treatment of metastatic brain disease with the following overall = objectives:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>To systematically review the evidence available for the = following=20 treatment comparisons for patients diagnosed with brain metastases = specifically addressing the following questions:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Do steroids improve neurologic symptoms in patients with=20 metastatic brain tumors compared to no treatment?</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>If steroids are given, what dose should be=20 used?</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>To make recommendations based on this evidence for the role of=20 corticosteroids in the management of these=20 patients.</TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane = Database=20 of Abstracts of Reviews of Effects. A broad search strategy using a = combination=20 of subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR2">2</A></CITE>].=20 Reference lists of included studies were also reviewed. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Eligibility criteria</DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English 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-control studies). = </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Study comparisons include one or more of the=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>steroid therapy versus none.</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>comparison of different doses of steroid=20 therapy.</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 = study arm=20 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 was used = to rate=20 the quality of randomized trials [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR4">4</A></CITE>].=20 The quality of comparative studies using non-randomized designs was = evaluated=20 using eight items selected and modified from existing scales as outlined = in=20 Appendix B of the Methodology chapter in this brain metastases guideline = series=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR2">2</A></CITE>].=20 </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 criteria endorsed by the = American=20 Association of Neurological Surgeons (AANS) and the Congress of = Neurological=20 Surgeons (CNS). These criteria are provided in the methodology paper of = this=20 guideline series. </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">Despite the widespread use of steroids in the management = of brain=20 metastases, only two publications met the stated eligibility criteria = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>].=20 Figure <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Fig1">1</A>=20 outlines the flow of studies through the review process. These two = studies are=20 outlined in the attached evidentiary table. In order to expand the = information=20 base for the =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=94=20 section of this chapter, additional searches were undertaken by = reviewing the=20 bibliographies of these two papers and additional review of the = published=20 literature addressing the treatment of metastatic brain disease for = references=20 to steroid administration. These articles are summarized in the =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=94.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_57_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/n11832031700653r/MediaObjects/= 11060_2009_57_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies </DIV> <HR> </DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Studies meeting search criteria</DIV> <DIV class=3DPara> <DIV class=3D"">The only two papers that met the search criteria are = summarized=20 below [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>].=20 The details are also summarized in the accompanying evidentiary table=20 (Table <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Tab1">1</A>).=20 In expanding the literature review to seek out additional supporting = information=20 for the "<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>"=20 portion of this document, we did not encounter any additional high = quality=20 studies specifically addressing the role of steroids in brain = metastases. This=20 was in agreement with several previous authors who upon review of the = topic have=20 encountered a lack of detailed, controlled accounts of steroid use in = the=20 studies under review, including the large randomized controlled trials = that=20 often form the basis of treatment decisions and recommendations = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>].<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Summary = of studies=20 meeting the systematic review eligibility criteria </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): Vecht et al. (1994), [<CITE><A=20 = href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 </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""><I>Study design</I> RCT (two trials reported) </P> <P class=3D""><I>Inclusion criteria for both RCTs</I> </P> <P class=3D"">KPS <U><</U> 80, histologically = confirmed=20 diagnosis of solid cancer outside nervous system, together with = single or=20 multiple BM diagnosed by CT </P> <P class=3D""><I>Exclusion criteria for both RCTs</I> </P> <P class=3D"">Age > 75 years; = KPS =3D 90 or 100;=20 prior RT to brain; likelihood of early treatment with = neurosurgery;=20 glucocorticoid administration in the previous 3 months; BM = secondary=20 to lymphoreticular malignancy; diabetes mellitus or disability due = to=20 causes other than BM </P> <P class=3D""><I>Interventions</I> </P> <P class=3D"">First RCT</P> <P class=3D""> G1: dexamethasone 8 mg/day=20 p.o. =D7 7 day (then tapered to discontinue)</P> <P class=3D""> G2: dexamethasone 16 mg/day=20 p.o. =D7 7 day (then tapered to discontinue)</P> <P class=3D"">Second RCT</P> <P class=3D""> After G1 versus G2 not significantly different = at day=20 7</P> <P class=3D""> G3: Dexamethasone 4 mg/day=20 p.o. =D7 28 day (then tapered to discontinue)</P> <P class=3D""> G4: Dexamethasone 16 mg/day=20 p.o. =D7 28 day (then tapered to discontinue)</P> <P class=3D""><I>Notes</I>: all pts scheduled for RT to started at = some=20 point after Day 7 </P> <P class=3D"">(RT dose/schedule not reported); all pts received = ranitidine=20 150 mg bid</P> <P class=3D""><I>Median follow-up</I>: not reported </P> <P class=3D""># <I>male</I>: </P> <P class=3D"">G1: 14/20; G2: 14/22; G3: 12/24; G4: 7/23</P> <P class=3D""><I>Median age (range)</I>: median not reported; mean = age =B1 SD: </P> <P class=3D"">G1: 61 =B1 7.6 years</P> <P class=3D"">G2: 61 =B1 11.5 years</P> <P class=3D"">G3: 60 =B1 9.9 years</P> <P class=3D"">G4: 56 =B1 10.9 years</P> <P class=3D""><I>Predominant tumor types</I>: </P> <P class=3D"">G1: lung 11/20, breast 4/20, gastrointestinal 4/20, = other=20 1/20</P> <P class=3D"">G2: lung 10/22, breast 6/22, kidney 3/22, = gastrointestinal=20 1/22</P> <P class=3D"">G3: lung 10/24, breast 7/24, kidney 3/24, = gastrointestinal=20 1/24</P> <P class=3D"">G4: lung 12/23, breast 5/23, gastrointestinal 2/23, = kidney=20 2/23</P> <P class=3D""># <I>of brain metastases</I>: </P> <P class=3D"">Not reported</P> <P class=3D""><I>Extra-cranial disease</I>: </P> <P class=3D"">Note reported</P> <P class=3D""><I>Baseline functional performance</I>: </P> <P class=3D"">Mean KPS =B1 SD (range)</P> <P class=3D""> G1: 58.5 =B1 11.8 (40=9680)</P> <P class=3D""> G2: 61.4 =B1 9.4 (50=9680)</P> <P class=3D""> G3: 65.0 =B1 10.6 (40=9680)</P> <P class=3D""> G4: 57.8 =B1 14.1(30=9680)</P></TD> <TD align=3Dleft> <P class=3D""><I>Primary outcome</I> </P> <P class=3D"">Change in KPS on day 7 from day 0</P> <P class=3D""><I>First RCT</I> </P> <P class=3D"">Mean (SD) absolute change in KPS at day 7:</P> <P class=3D"">G1: 8.0 =B1 10.1; G2: = 7.3 =B1 14.2=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts with improved KPS on day 7:</P> <P class=3D"">G1: 60%; G2: 54%</P> <P class=3D"">Mean (SD) absolute change in KPS at day 28:</P> <P class=3D"">G1: 6.7 =B1 18.4; G2: = 13.8 =B1 14.5=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts with improved KPS on day 28:</P> <P class=3D"">G1: 53%; G2: 81%</P> <P class=3D""><I>Second RCT</I> </P> <P class=3D"">Mean (SD) absolute change in KPS at day 7:</P> <P class=3D"">G3: 6.7 =B1 11.3; G4: = 9.1 =B1 12.4=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts with improved KPS on day 7:</P> <P class=3D"">G3: 67%; G4: 70%</P> <P class=3D"">Mean change in KPS (SD) at day 28</P> <P class=3D"">G3: 7.1 =B1 18.2; G4: = 5.6 =B1 18.5=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts improved:</P> <P class=3D"">G3: 62%; G4: 50%</P> <P class=3D""><I>Adverse events: reported combined results</I> = </P> <P class=3D"">Toxic effects more frequent in G2 + G4 = (16 mg)=20 (<I>P</I> < 0.03) </P> <P class=3D"">Incidence of cushingoid facies or ankle edema = increased with=20 duration of treatment (<I>P</I> =3D 0.02 at day 7 and=20 <I>P</I> =3D 0.03 at day 28) and with higher doses of=20 dexamethasone </P> <P class=3D""><I>At day 28</I>: reported combined results from = both RCTs=20 </P> <P class=3D"">Raised glucose:</P> <P class=3D"">G1: 25%; G2/G4: 21%; G3: 18%</P> <P class=3D"">Raised blood pressure:</P> <P class=3D"">G1: 12%; G2/G4: 26%; G3: 45%</P> <P class=3D"">Infectious disease:</P> <P class=3D"">G1: 6%; G2/G4: 9%; G3: 9%</P> <P class=3D"">Gastrointestinal complaints:</P> <P class=3D"">G1: 6%; G2/G4: 24%; G3: 18%</P> <P class=3D"">Mental changes:</P> <P class=3D"">G1: 19%; G2/G4: 21%; G3: 14%</P> <P class=3D"">Ankle edema:</P> <P class=3D"">G1: 13%; G3: 14%; G2/G4: 26%</P> <P class=3D"">Cushingoid facies:</P> <P class=3D"">G1: 69%; G3: 32%; G2/G4: 65%</P> <P class=3D"">Proximal weakness:</P> <P class=3D"">G1: 38%; G3: 14%; G2/G4: 38%</P></TD> <TD align=3Dleft> <P class=3D""><I>AANS/CNS evidence classification: Class 1</I> = </P> <P class=3D""><I>Due to the relatively small size, heterogeneity = in study=20 design and lack of clarity in the statistical presentation and = analysis=20 there are concerns about over generalizing the results and = conclusions of=20 this trial.</I> </P></TD></TR></TBODY></TABLE> <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): Wolfson et al. (1994), = [<CITE><A=20 = href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>]=20 </P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""><I>Study design</I>: prospective randomized phase II = trial=20 [stratified by response to high-dose dexamethasone] </P> <P class=3D""><I>Inclusion criteria</I> </P> <P class=3D"">Measurable BM on CT; histologically confirmed = primary=20 malignancy; granulocyte counts >1,000/mm<SUP>3</SUP> and serum = glucose=20 <300 mg% </P> <P class=3D""><I>Exclusion criteria</I> </P> <P class=3D"">Primary malignancies including lymphomas, germ cell = tumors,=20 primary CNS tumors, SCLC, multiple primaries, and unknown = primaries;=20 resected BMs; illnesses such as active peptic ulcer disease, = uncontrolled=20 diabetes mellitus (serum glucose ≥ 300 mg%), = adrenal=20 insufficiency or being seropositive for HIV </P> <P class=3D"">prior cranial RT; administration of steroid therapy = more than=20 24 h prior to study entry</P> <P class=3D""><I>Interventions</I> </P> <P class=3D"">G1: dexamethasone 24 mg i.v. every 6 h for = 48 h=20 prior to WBRT; then dexamethasone 4 mg p.o. every 6 h = for=20 2 weeks during WBRT</P> <P class=3D"">G2: dexamethasone 24 mg i.v. every 6 h for = 48 h=20 prior to WBRT</P> <P class=3D""><I>Doses</I> </P> <P class=3D"">G1: WBRT: 30 Gy at 3 Gy/fraction</P> <P class=3D"">G2: WBRT: 30 Gy at 3 Gy/fraction</P> <P class=3D""><I>Note</I>: all pts given H-2 blockers during = steroid=20 administration and oral phenytoin for seizure prophylaxis </P> <P class=3D""><I>Median follow-up</I>: not reported </P> <P class=3D""># <I>male</I> </P> <P class=3D"">G1: 2/7; G2: 3/5</P> <P class=3D""><I>Median age (range)</I>: not reported by treatment = group=20 </P> <P class=3D"">Overall median age: 58 years</P> <P class=3D""><I>Tumor type</I> </P> <P class=3D"">G1: NSCLC 5/7, breast 2/7</P> <P class=3D"">G2: NSCLC 3/5, breast 1/5, bladder 1/5</P> <P class=3D""># <I>of brain metastases</I> </P> <P class=3D"">G1: 1 BM 2/7, 2 BM 4/7, >2 BM 1/7</P> <P class=3D"">G2: 1 BM 2/5, 2 BM 1/5, >2 BM 2/5</P> <P class=3D""><I>Extra-cranial disease</I>: Extra-cranial = metastases: </P> <P class=3D"">G1: 5/7; G2: 3/5</P> <P class=3D""><I>Baseline functional performance</I> </P> <P class=3D"">Not reported</P></TD> <TD align=3Dleft> <P class=3D""><I>Primary outcome</I> </P> <P class=3D"">Overall survival</P> <P class=3D""><I>Survival</I> </P> <P class=3D"">Overall median survival: 4 months (no between = group=20 statistical analyses due to limited pt numbers)</P> <P class=3D""><I>Functional performance</I> </P> <P class=3D"">Change in general performance status:</P> <P class=3D"">G1: improved 2/7, deteriorated 1/7, no change = 4/7</P> <P class=3D"">G2: improved 0/5, deteriorated 1/5, no change = 4/5</P> <P class=3D"">Change in neurological function class:</P> <P class=3D"">G1: improved 1/7, deteriorated 1/7, no change = 5/7</P> <P class=3D"">G2: improved 0/5, deteriorated 1/5, no change = 4/5</P> <P class=3D""><I>Cause of death</I> </P> <P class=3D"">Non-specific and not reported by treatment group</P> <P class=3D""><I>Adverse events/other</I> </P> <P class=3D"">Transient hyperglycemia: 1/12</P></TD> <TD align=3Dleft> <P class=3D""><I>AANS/CNS evidence classification</I>: <I>class = 1</I> </P> <P class=3D""><I>Despite this qualifying as class I the small size = and lack=20 of any statistical analysis render this article useless for any=20 recommendations.</I> </P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>Abbreviations</I>: <I>BM</I> brain metastases, = <I>CNS</I>=20 central nervous system, <I>G1</I> Group 1, <I>G2</I> Group 2, <I>G3</I> = Group 3,=20 <I>G4</I> Group 4, <I>KPS</I> Karnofsky performance score, <I>NSCLC</I>=20 non-small cell lung cancer, <I>NR</I> not reported, <I>Pts</I> patients, = <I>RCT</I> randomized control trial, <I>RT</I> radiotherapy, <I>SCLC</I> = small=20 cell lung cancer, <I>SD</I> standard deviation, <I>WBRT</I> whole-brain=20 radiation therapy </DIV></DIV></DIV></DIV></DIV> <P class=3D"">The first of the two studies to meet the search criteria = described a=20 randomized study of 4, 8 and 16 mg/day dosing of dexamethasone and = found no=20 advantage to higher dosing in patients who were not felt to be in = impending=20 danger of cerebral herniation [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>].=20 Vecht et al., published their findings from two consecutively executed=20 double-blind randomized trials in patients with brain metastases and = Karnofsky=20 performance scores (KPS) of 80 or less which were designed to evaluate = the=20 minimum effective dose of oral dexamethasone. Initially a dexamethasone = dosage=20 of 8 mg/day (Group 1) was compared to 16 mg/day (Group 2), = followed by=20 a comparison of 4 mg/day (Group 3) versus 16 mg/day (Group 4). = The=20 outcomes of interest were alteration in KPS and the frequency of side = effects at=20 days 0, 7, 28, and 56. </P> <P class=3D"">In the initial study, although both groups showed an = improvement,=20 there was no significant difference in KPS improvement comparing the = 8-mg group=20 versus the 16-mg group at day 7 (mean 8.0 =B1 10.1 versus = 7.3 =B1 14.2). At the 28 day point, there was a larger = but still=20 non-significant rate of improvement thought to be biased by earlier = steroid=20 tapering in the lower group. </P> <P class=3D"">In the second trial, again both groups showed improvement. = However,=20 no significant difference between the 4- and 16-mg group (comparing=20 6.7 =B1 11.3 points at day 7 and 7.1 =B1 18.2 = points at=20 day 28, versus 9.1 =B1 12.4 and 5.6 =B1 18.5 = points,=20 respectively) could be detected. Side effects (Cushingoid changes and = extremity=20 edema) occurred more frequently in the 16 mg/day versus the = 4 mg/day=20 group at Day 28 (Combined frequency 91% versus 46%,=20 <I>P</I> < 0.03). </P> <P class=3D"">The authors conclude that for the majority of patients, = the lower=20 doses of 4 and 8 mg dexamethasone per day have an equivalent effect = on=20 improving neurologic performance when compared to a dose of = 16 mg/day at 1=20 and 4 weeks of treatment, in moderately symptomatic patients = without signs=20 of impending herniation. A non-significant trend toward improvement at=20 28 days was noted with the higher dosage. The authors postulated = that the=20 early taper in the lower dosage group led to an increase in recurrence = of=20 symptoms that may have increased this apparent effect. The dosing = recommendation=20 from this study resulted in a set 4 mg/day dosage with a dose taper = for=20 28 days in patients with no symptoms of mass effect used for the = second=20 study. </P> <P class=3D"">Side effects appeared to be dose-dependent, occurring more = frequently in patients using 16 mg/day. Therefore, the authors = concluded=20 that steroid related toxicity was increased with the higher daily = dosage.=20 Although the study is double blind and randomized, the relatively small = size,=20 inconsistencies in the design and lack of clarity in the presentation of = the=20 data and analysis are concerns. Nonetheless, this work appears to be the = most=20 detailed and informative available to assist with formulating treatment=20 recommendations. The data, while extremely limited, support a set of = treatment=20 recommendations which follow a general trend toward higher steroid = dosages in=20 symptomatic patients exhibiting greater mass effect symptoms of = increased=20 intracranial pressure, as opposed to lower doses of steroids for = asymptomatic=20 patients. </P> <P class=3D"">Wolfson et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>]=20 prospectively studied 12 patients with histologically confirmed = malignancies and=20 radiographically documented brain metastases and attempted to evaluate = the=20 indications for glucocorticoids. Patients were scored for general = performance=20 status and neurologic function class. All subjects received 24 mg = of=20 intravenous dexamethasone every 6 h for 48 h and after an = assessment,=20 were randomized to receive either 4 mg of oral dexamethasone every = 6 h=20 (Group 1) or no steroids (Group 2) during radiotherapy (30 Gy in = ten=20 fractions). Prior to randomization, five (33%) had a positive response = and eight=20 (67%) had no response to the high dose level. Seven patients were = randomized to=20 continue receiving steroids at the reduced level and five received none = during=20 radiotherapy. The change in general performance status for Group 1 was: = Improved=20 2/7 (29%), deteriorated 1/7 (15%), no change 4/7 (57%). For Group 2, the = change=20 in performance status was: Improved 0/5 (0%), deteriorated 1/5 (20%) and = no=20 change 4/5 (20%). The change in neurological function for Group 1 was: = Improved=20 1/7 (14%), deteriorated 1/7 (14%), no change 5/7 (72%); change in = neurological=20 function for Group 2 was: Improved 0/5 (0%), deteriorated 1/5 (20%), no = change=20 4/5 (80%). No statistical analysis was performed due to the small sample = size.=20 The authors conclude that the specific role of steroids in treating = patients=20 with metastatic carcinoma to the brain remains uncertain and should be = evaluated=20 in a cooperative prospective trial. Due to the small size and lack of = any=20 statistical analysis, it is impossible to reach any conclusion based on = this=20 study; therefore, no recommendations will be made based on this small = trial.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Role of steroids in metastatic brain disease</DIV> <P class=3D"">Given the extremely limited number of studies which = satisfied the=20 conditions of our search criteria, an additional discussion of published = literature on the subject of corticosteroids in metastatic brain disease = is=20 provided to offer a larger context for this topic. While the following = studies=20 were not part of the body of evidence considered in formulating = treatment=20 recommendations in our evidence-based guidelines, they do highlight = areas of=20 interest where clinical trials are still required to answer important=20 steroid-related questions. </P> <P class=3D"">A review of the outcomes in the Radiation Therapy Oncology = Group=20 (RTOG) studies examining various radiotherapeutic regimens for patients = with=20 metastatic brain disease demonstrated a dramatic early improvement in = patients=20 treated concurrently with steroids during the early phases of the trials = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>].=20 However, as the authors note, the administration of steroids was not = well=20 controlled in these studies and was not a primary point of interest so, = although=20 these observations contributed to the overall clinical impression that = steroids=20 were of benefit in the adjuvant treatment of brain metastases, it is = difficult=20 to extrapolate treatment recommendations from these studies. In Borgelt = et al.,=20 this is shown by the fact that symptomatic patients receiving steroids = had a=20 significant improvement in neurological function as opposed to those who = did not=20 receive steroids. None of these studies suggested that the use of = steroids=20 halted time to progression. </P> <P class=3D"">Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>]=20 published an American College of Radiology (ACR) Committee on = Appropriateness=20 Criteria consensus report following an expert panel review on the=20 pre-irradiation evaluation and management of brain metastases. The = authors cite=20 six articles to support the generation of their expert opinions = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 They initially note that although clinical experience has established = the=20 effectiveness of corticosteroids in reducing symptoms and radiographic=20 peritumoral edema, controversy remains on the specific indications and = dosage=20 used. They point out that the earliest studies to support steroid use = prior to=20 radiotherapy used radiation dosing schemes that are presently atypical = and that=20 there was evidence that steroids were only indicated when there was a = concern=20 about raised intracranial pressure [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR12">12</A></CITE>].=20 In one study, 27% of patients who received 10 Gy of single fraction = whole=20 brain radiotherapy (WBRT) experienced signs of increased intracranial = pressure=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR12">12</A></CITE>].=20 They also note evidence from one trial indicating that patients who were = moderately symptomatic who received steroid therapy during radiation = experienced=20 a more rapid improvement in their clinical symptoms, although there was = no=20 impact on progression-free or overall survival. This review went onto = outline=20 several papers addressing the acute and chronic side effects and the = studies=20 that address dosing and toxicity [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 </P> <P class=3D"">This consensus review summarizes the authors=92 views on = steroid use=20 for metastatic brain disease by indicating that the patient who shows = evidence=20 of elevated intracranial pressure, but who does not require immediate = surgical=20 attention for either hydrocephalus or impending herniation, should = receive=20 4=966 mg/day of dexamethasone in divided doses and that the routine = use of=20 corticosteroids in patients without neurological symptoms is not = necessary.=20 </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Effect of steroids on radiographic edema</DIV> <P class=3D"">In 1982, Hatam et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR14">14</A></CITE>]=20 prospectively studied the effect of dexamethasone therapy on peritumoral = edema=20 based on computed tomography (CT) describing specifically three cases of = metastatic intracranial disease in which a linear decrease in edema = volume was=20 observed, reducing the measured volume of edema to one-fourth of the = initial=20 volume after 2 weeks of treatment starting with 4 mg four = times daily=20 and tapered to 1 mg/day. The exact time course for the metastatic = patients=20 was not reported separately but the authors did report a substantial = clinical=20 improvement in these patients they felt was associated with the use of=20 dexamethasone. </P> <P class=3D"">Andersen et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR11">11</A></CITE>]=20 published a subsequent report in 1994 that quantified the effect of = steroid=20 therapy over time on peritumoral brain edema in vivo using a magnetic = imaging=20 based technique. Magnetic resonance based assessments of peritumoral = edema were=20 undertaken on 23 brain tumor patients including 13 with brain metastases = at=20 baseline and at Days 1, 3 and 7 after starting steroid therapy. = Intravenous=20 dexamethasone was used at dose of 0.26=960.64 mg/kg (for a = 70 kg patient=20 this range is 20=9645 mg/day). After 7 days of steroid = treatment the=20 total edema area was reduced by 10.3% in the metastatic patients, with = an=20 average reduction in mean volume of 4.6% after 24 h of treatment = and 13.5%=20 after 7 days. This effect was observed for up to 63 days and = it was=20 demonstrated that after 40=9663 days (6=969 weeks) of steroid = therapy the=20 peritumoral water content was close to the upper normal range for white = matter.=20 The authors concluded that steroids significantly reduce the volume of=20 peritumoral edema in patients with metastatic brain disease even after a = few=20 days of treatment. They postulate a mechanism of steroid-induced = reduction in=20 edema below the level of absorption and commented that they thought they = may=20 have obtained the same effects with a dose-reduction to minimize = potential side=20 effects. </P> <P class=3D"">Minamikawa et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR15">15</A></CITE>]=20 studied the effect of glucocorticoid treatment (methylprednisolone, dose = not=20 specified) on the apparent diffusion coefficient (ADC) imaging in a = series of 13=20 patient including four with metastatic brain disease. Although it is not = possible to examine the effects on the metastatic patients separately, = the=20 authors suggested that ADC imaging was a more sensitive technique than=20 conventional MRI imaging for studying the effects of steroids on = peritumoral=20 edema, even in the absence of detectable MRI changes. </P></DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>Dosing and toxicity</DIV> <P class=3D"">Hempen et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>]=20 retrospectively reviewed 138 consecutive patients to evaluate the impact = of=20 dosage and duration of dexamethasone administration during radiation = therapy for=20 patients with both primary and metastatic brain tumors = (n =3D 91). The=20 dosage of dexamethasone was gradually reduced from an initial median = dose of=20 7=9612 mg/day to a median of 1=966 mg/day with an average = duration of=20 7 weeks for the metastatic group. The authors reported a period of = initial=20 clinical improvement with relatively few side effects. Specifically, 33% = of=20 patients reported improvement in symptoms with steroid use prior to=20 radiotherapy, 44% during radiotherapy and 11% following radiotherapy. = However,=20 as dexamethasone was continued, this trend reversed and less symptom = relief was=20 observed with increasing toxicity. Life-threatening complications were = rare.=20 Side effects attributed to steroid use included: hyperglycemia (47%), = peripheral=20 edema (11%), psychiatric disorder (10%), candidiasis (7%), Cushing=92s = syndrome=20 (4%), muscular weakness (4%) and pulmonary embolus (2%). Of a cohort of = 13=20 clinically asymptomatic patients who received no dexamethasone during=20 radiotherapy, 12 (92%) showed no sign of worsening neurological = problems. The=20 patient with worsened symptoms had brain stem involvement. The authors = conclude=20 that dexamethasone effectively minimizes neurological symptoms and = radiation=20 therapy related side effects in patients with both primary and secondary = brain=20 tumors. The toxicity of dexamethasone was noted to increase over time = and=20 therefore a patient-specific dosing pattern and taper was recommended. = The=20 authors suggested that a prospective study specifically addressing the = relative=20 balance of symptom relief versus toxicity would be of benefit and that = there is=20 little evidence to support the use of steroids in the asymptomatic = patient. </P> <P class=3D"">In 1999, Lagerwaard et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR8">8</A></CITE>]=20 published an extensive retrospective review of 1,292 patients with = metastatic=20 brain disease referred to a single institution to identify prognostic = (risk)=20 factors. The majority of patients were treated with WBRT = (n =3D 1,079,=20 84%); 118 (9%) were treated with steroids only and 95 (7%) with surgery = and=20 radiotherapy. Data obtained included: age, sex, performance status, = number and=20 distribution of brain metastases, site of primary tumor, histology, = interval=20 between primary tumor and brain metastases, systemic tumor activity, = serum=20 lactate dehydrogenase, response to steroid treatment, and treatment = modality.=20 Dexamethasone was used in a dose range of 4=9616 mg/day (mean = dosage=20 14.6 mg/day), which was =93tapered slowly and discontinued in the = weeks=20 following therapy=94 (specific details not stated). </P> <P class=3D"">Response to steroid therapy was judged retrospectively, = from review=20 of the medical records, as good (marked improvement), moderate (some=20 improvement) or little (little or no improvement). Both univariate and=20 multivariate analyses were performed. The overall median survival was=20 3.4 months, with 6 month, 1, and 2 year survival = percentages of=20 36, 12, and 4%, respectively. Median survival was 1.3 months in = patients=20 treated with steroids only, 3.6 months in patients treated with=20 radiotherapy, and 8.9 months in patients treated with surgical = resection=20 followed by radiotherapy (all comparisons = <I>P</I> < 0.0001). </P> <P class=3D"">Multivariate analysis confirmed the previously reported = observation=20 that the impact of treatment modality on survival in patients with brain = metastases was the most significant single factor in predicting = survival.=20 However, response to steroid treatment, performance status, systemic = tumor=20 activity and serum lactate dehydrogenase levels were also all = independent=20 prognostic factors on survival, second only to treatment modality in = level of=20 significance. Site of primary tumor, age, and number of brain metastases = were=20 also identified as prognostic factors. </P> <P class=3D"">The authors concluded that the strongest prognostic (risk) = factors=20 were choice of treatment modality, response to steroids, performance = status, and=20 evidence of systemic disease and they proposed using these classifiers = in=20 identifying favorable and unfavorable subgroups of patients with brain=20 metastases for future studies. </P> <P class=3D"">Millar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>]=20 attempted to assess the impact of steroid therapy in the management of = brain=20 metastases by undertaking a systematic review of published randomized = trials on=20 WBRT for multiple cerebral metastases. In this extensive review = published in=20 2004, the authors identified 21 full manuscripts of published randomized = controlled trials involving WBRT in the treatment of multiple brain = metastases=20 from 1971 to 2003. They attempted to extract details on the use and type = of=20 steroid, timing of steroids relative to radiotherapy, response = assessment and=20 contribution of steroids to overall outcome. They reported that 18 of = the 21=20 trials reviewed documented steroid use. Overall survival was an outcome = assessed=20 in all studies. Thirteen studies assessed neurological response and ten = assessed=20 a radiographic endpoint. Ten of the studies (48%) suggested a positive = effect of=20 steroid use on the outcome assessed. Only one study=97in the palliative=20 setting=97provided a fixed steroid dose. </P> <P class=3D"">The authors concluded that the reporting of steroid use in = previously published randomized trials assessing treatment for patients = with=20 brain metastases is =93non-uniform and not sufficiently detailed=94 = making it=20 difficult to assess the treatment effect. They call for a more standard = approach=20 to steroid dose in future studies or at a minimum better reporting of = dosages=20 used to better determine symptom response and durability of response. = They also=20 note that side effects of steroid use and the ability to taper off = steroids=20 after treatment intervention are additional outcomes of interest in the = planning=20 of future studies. </P> <P class=3D"">Weissman et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR16">16</A></CITE>]=20 published their experience with a treatment regimen designed to reduce = steroid=20 toxicity in 20 patients with newly diagnosed brain metastases. All = patients=20 received dexamethasone starting at 8 mg twice daily for 4 days = then=20 4 mg twice daily for 4 days followed by 2 mg twice daily = until=20 the last day of radiation therapy. Radiation dose and schedules ranged = from=20 20 Gy in five fractions to 58 Gy in 29 fractions. Fourteen = patients=20 (70%) received dexamethasone for a minimum of 24 h before their = first=20 radiation treatment and seven of those patients (50%) experienced = improvement in=20 neurologic symptoms and signs before radiotherapy. Fourteen patients = (70%)=20 completed the entire course of radiation and dexamethasone as planned. = One=20 patient required reinstitution of dexamethasone within 30 days of = finishing=20 radiation for neurological decline. The authors felt that the = twice-daily dose=20 was well tolerated. Steroid related toxicity included hyperglycemia = (5%),=20 candida esophagitis (5%), steroid pseudorheumatism (10%), peripheral = edema (5%)=20 and steroid withdrawal syndrome (5%). </P> <P class=3D"">In 2006, the results of a series of systematic reviews = with the=20 stated purpose =93to establish evidence-based guidelines and identify=20 controversies regarding the management of patients with brain = metastases=94 was=20 published by Soffietti et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>].=20 This was conducted by a multi-disciplinary task force of the European = Federation=20 of Neurological Societies and includes a review of data obtained from = the=20 Cochrane Library, bibliographic databases, overview papers and previous=20 guidelines from scientific societies and organizations. Under the = section on=20 supportive care and steroids only one original article is cited and = reviewed,=20 and that is the publication by Vecht [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>],=20 which also met the eligibility criteria for this guideline paper and is=20 discussed extensively in the scientific foundation section. This paper = was used=20 to support the recommendation that, in most cases, initial dexamethasone = doses=20 should not exceed 4=968 mg/day. However, in patients with more = severe=20 symptoms related to increased intracranial pressure doses of = 16 mg/day or=20 higher should be considered (Level of Evidence B) [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR17">17</A></CITE>].=20 The remainder of the recommendations were based on uniform consensus of = the task=20 force (referred to as a =93Good Practice Point=94) and are summarized = below.=20 Dexamethasone was noted as the corticosteroid of choice and twice daily = dosing=20 was thought to be sufficient (Good Practice Point). Tapering of steroid = dosing=20 within 1 week of starting therapy and discontinuation within = 2 weeks=20 if possible was encouraged (Good Practice Point). Finally, patients who = do not=20 have signs or symptoms of increased intracranial pressure do not have to = be=20 treated with steroids (Good Practice Point). </P> <P class=3D"">Given the very limited number of studies that met the = inclusion=20 criteria for the systematic literature review on the role of steroids in = metastatic brain disease, we are unable to propose specific guidelines = on many=20 of the issues of central interest to the treating physician. </P> <P class=3D"">In summarizing the <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=20 section above we are able to offer the following observations: first, = Overall=20 the literature favors the position that corticosteroids are of benefit = in=20 providing temporary symptomatic relief of CNS symptoms related to = increased=20 intracranial pressure and edema secondary to brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 Secondly, dexamethasone is the steroid most often used, with the = rationale that=20 it has limited mineralocorticoid effects. Other steroids have been used = with=20 similar reported clinical responses. Dosing has been recommended to be=20 sufficient at twice daily although more frequent dosing has been = suggested with=20 increasing concern for raised intracranial pressure and impending = herniation=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR14">14</A></CITE>].=20 Finally, based primarily on the asymptomatic patients in the study by = Hempen et=20 al., it is the opinion offered in the available studies that = asymptomatic=20 patients do not require steroids [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 Numerous authors cite concerns for the toxicity of steroid therapy and = due to=20 the lack of a uniform recommendation on dosing and the apparent = complexity of=20 the response in individual patients it has been recommended that dose = reduction=20 be considered within 1 week of initiation of treatment. The dose = reduction=20 appears to often require alteration in individual patients due to the = diversity=20 of response [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR16">16</A></CITE>].=20 </P> <P class=3D"">An interesting observation in the review of the literature = on this=20 subject is the number of authors who appear to assume that steroids are = a=20 mainstay of treatment for the patient with metastatic brain disease = despite the=20 relative lack of detailed information available to guide specific = therapy. In=20 general, the evidence for specific dosages and regimens of steroids are = poorly=20 detailed. On the other hand, there is very little information provided = in the=20 literature that suggests that steroids are of no benefit in this patient = population with the exception of the asymptomatic patient. </P> <P class=3D"">Given the general consensus in the literature that = steroids are of=20 benefit in selected patients with metastatic brain disease and the = frequent=20 observation that dosing needs to be specifically tailored to the = individual, it=20 appears unlikely that in depth studies specifically addressing this = issue will=20 be forthcoming. However, the need for additional recommendations for = dosing and=20 duration of therapy may result in an increased awareness of this concern = and=20 potentially an alteration of clinical trials designed to address = comparisons.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Summary and conclusions</DIV> <P class=3D"">In terms of articles meeting the search criteria described = in the=20 methods section above, the study by Vecht et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 stands alone in providing the most convincing data on the role for = steroids in=20 patients with brain metastases and for the choice of dosing. Based on = their=20 observations of improvement in all groups treated with steroids, a level = 3=20 recommendation can be made as follows: </P> <DIV class=3D""><A name=3DSec15></A> <DIV class=3DHeading3>Steroid therapy versus no therapy</DIV> <P class=3D"">Corticosteroids are recommended to provide temporary = symptomatic=20 relief of CNS symptoms related to increased intracranial pressure and = edema=20 secondary to brain metastases. (Level 3 recommendation). Dexamethasone = is the=20 corticosteroid of choice, mainly because of its limited = mineralocorticoid=20 effects, and should be tapered slowly over several weeks to avoid = rebound=20 symptoms. </P> <P class=3D"">The Vecht et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 article provides evidence that the administration of steroids provides = relief of=20 symptoms in patients with symptomatic brain metastatic disease; however, = recognizing that there is no control group (a =93no treatment group=94) = only the=20 lowest grade of recommendation can be made. </P> <P class=3D"">Vecht et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 also conclude that a starting dose of 4=968 mg/day be considered, = unless=20 patients exhibit severe symptoms consistent with increased intracranial=20 pressure. They further recommended that those patients at high risk for = severe=20 consequences from raised intracranial pressure be considered for more = aggressive=20 dosing on the order of doses of 16 mg/day or higher. This study is = relied=20 upon heavily in the systematic review and consensus reports summarized = in the=20 "<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>"=20 section above [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>].=20 However, the number of patients involved is relatively small and the = study lacks=20 a validation group; thus, despite the randomized design and ranking = yielding a=20 higher class of evidence, the recommendation itself is downgraded to = reflect=20 these concerns. Based on this study design and results, the following=20 recommendation can be made. </P></DIV> <DIV class=3D""><A name=3DSec16></A> <DIV class=3DHeading3>Comparison of different doses of steroid = therapy</DIV> <P class=3D"">It is recommended for patients who are symptomatic from = metastatic=20 brain disease that a starting dose of 4=968 mg/day of dexamethasone = be=20 considered, unless patients exhibit severe symptoms consistent with = increased=20 intracranial pressure. In these patients it is recommended that higher = doses=20 such as 16 mg/day or more be considered. (Level 3 recommendation)=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec17></A> <HR> <DIV class=3Dheading2>Key issues for further investigation</DIV> <DIV class=3DPara> <DIV class=3D"">Given the number of patients who receive steroids as a = portion of=20 their care for treating the signs and symptoms of brain metastases, the = medical=20 literature contains relatively few detailed reports specifically = addressing this=20 issue. It may be that the early observation that there was little effect = on=20 overall survival has limited the subsequent level of interest in this = issue.=20 Review of the literature finds that the majority of authors on the = subject feel=20 that there is a symptomatic benefit from the use of systemic steroids in = the=20 management of these patients. It is not clear that there is an urgent = need for=20 randomized trials specifically addressing the issue of steroid dosing = and=20 toxicity. However, future studies could be planned to allow better = control,=20 recording and analysis of steroid dosing and response to allow a more = robust=20 analysis of the risk to benefit ratio of various dosing regimens. This = would=20 potentially optimize the benefits while limiting the side effects, which = could=20 lead to an improvement in overall outcome in addition to improving = quality of=20 life measures in the short term.=20 <BLOCKQUOTE> <P class=3D""><I>No ongoing or recently closed clinical trials on the = use of=20 steroids for the management of brain metastases were found that met = the=20 eligibility criteria.</I> </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>Reference </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Soffietti R, Cornu P, Delattre JY, Grant R, = Graus F,=20 Grisold W et al (2006) EFNS guidelines on diagnosis and treatment = of brain=20 metastases: report of an EFNS task force. 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From: Subject: 10.1007/s11060-009-0057-4 Date: Fri, 18 Dec 2009 19:26:46 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0044_01CA8018.09B4E160" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0044_01CA8018.09B4E160 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/n11832031700653r/fulltext.html 10.1007/s11060-009-0057-4</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.16945" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0057-4</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Invited Manuscript</H2> <DIV class=3DHeading1><A name=3Dtitle></A>The role of steroids in the = management of=20 brain metastases: a systematic review and evidence-based clinical = practice=20 guideline </DIV> <P class=3DAuthorGroup>Timothy C. Ryken<SUP>1</SUP>,=20 Michael McDermott<SUP>2</SUP>, = Paula D. Robinson<SUP>3</SUP>,=20 Mario Ammirati<SUP>4</SUP>, David W. Andrews<SUP>5</SUP>, = Anthony L. Asher<SUP>6</SUP>, = Stuart H. Burri<SUP>7</SUP>,=20 Charles S. Cobbs<SUP>8</SUP>, = Laurie E. Gaspar<SUP>9</SUP>,=20 Douglas Kondziolka<SUP>10</SUP>, = Mark E. Linskey<SUP>11</SUP>,=20 Jay S. Loeffler<SUP>12</SUP>, = Minesh P. Mehta<SUP>13</SUP>,=20 Tom Mikkelsen<SUP>14</SUP>, = Jeffrey J. Olson<SUP>15</SUP>,=20 Nina A. Paleologos<SUP>16</SUP>,=20 Roy A. Patchell<SUP>17</SUP> and=20 Steven N. Kalkanis<SUP>18 <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#ContactOfAuthor18"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/n11832031700653r/contact.gif" = border=3D0></A></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurosurgery, 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=3DAff2></A>(2) </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=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>McMaster University Evidence-Based = Practice=20 Centre, Hamilton, ON, 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 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=3DAff14></A>(14) </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=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, Northshore = University=20 Health System, Evanston, IL, 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 Neurology, Barrow = Neurological=20 Institute, Phoenix, AZ, 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/n11832031700653r/contact.gif" = border=3D0></TD> = <TD><STRONG>Steven </STRONG><STRONG>N. </STRONG><STRONG>Kalkani= s</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:kalkanis@neuro.hfh.edu">kalkanis@neuro.hfh.edu</A><BR><STR= ONG>Email:=20 </STRONG><A=20 = href=3D"mailto:skalkan1@hfhs.org">skalkan1@hfhs.org</A></TD></TR></TBODY>= </TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>8 September 2009 <STRONG>Accepted:=20 </STRONG>8 November 2009 <STRONG>Published online:=20 </STRONG>3 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN = class=3DAbstractHeading>Abstract</SPAN> <DIV class=3DAbstractSection> <DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20 name=3DASec1></A><B>Question</B> </SPAN>Do steroids improve = neurologic=20 symptoms in patients with metastatic brain tumors compared to no = treatment? If=20 steroids are given, what dose should be used? Comparisons include: (1) = steroid=20 therapy versus none. (2) comparison of different doses of steroid = therapy.=20 <DIV class=3DAbstractPara> <DIV class=3D""><B>Target population</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">These recommendations apply to adults diagnosed with = brain=20 metastases.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B>Recommendations</B> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><B><I>Steroid therapy versus no steroid therapy</I></B>=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Asymptomatic brain metastases patients without mass = effect</I>=20 </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Insufficient evidence exists to make a treatment = recommendation=20 for this clinical scenario.</DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Brain metastases patients with mild symptoms related = to mass=20 effect</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Corticosteroids are recommended to = provide=20 temporary symptomatic relief of symptoms related to increased = intracranial=20 pressure and edema secondary to brain metastases. It is recommended for = patients=20 who are symptomatic from metastatic disease to the brain that a starting = dose of=20 4=968 mg/day of dexamethasone be considered. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Brain metastases patients with moderate to severe = symptoms=20 related to mass effect</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Corticosteroids are recommended to = provide=20 temporary symptomatic relief of symptoms related to increased = intracranial=20 pressure and edema secondary to brain metastases. If patients exhibit = severe=20 symptoms consistent with increased intracranial pressure, it is = recommended that=20 higher doses such as 16 mg/day or more be considered. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Choice of Steroid</I> </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> If corticosteroids are given, = dexamethasone is the=20 best drug choice given the available evidence. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Duration of Corticosteroid Administration</I> = </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D""><I>Level 3</I> Corticosteroids, if given, should be = tapered slowly=20 over a 2 week time period, or longer in symptomatic patients, based = upon an=20 individualized treatment regimen and a full understanding of the = long-term=20 sequelae of corticosteroid therapy. </DIV></DIV> <DIV class=3DAbstractPara> <DIV class=3D"">Given the very limited number of studies (two) which met = the=20 eligibility criteria for the systematic review, these are the only=20 recommendations that can be offered based on this methodology. Please = see =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=94=20 and =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec14">Summary</A>=94=20 section for additional details. </DIV></DIV></DIV></DIV></DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Brain=20 metastases - Steroids - Neurologic=20 symptoms - Steroid dosage - 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"">Glucocorticoids have typically been used to assist in = controlling=20 cerebral edema in the early supportive care of the patient with newly = diagnosed=20 metastatic brain disease. Dexamethasone is generally considered the = steroid of=20 choice because of its minimal mineralocorticoid effect and long = half-life,=20 although any other corticosteroid can be effective if given in = equipotent doses.=20 Steroids have been used alone for palliation of symptoms and in = combination with=20 radiotherapy as an initial course of therapy. A review of the available=20 literature indicates that the majority of these patients have been = managed with=20 starting doses of 4=968 mg/day and it has been stated that up to = 75% of=20 patients with brain metastases show marked neurological improvement = within=20 24=9672 h after beginning dexamethasone [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>].=20 However, side effects from chronic dexamethasone administration, = including=20 myopathy, are frequent and contribute to disability. Asymptomatic or = minimally=20 symptomatic patients may benefit little from the routine administration = of=20 steroid therapy and be exposed to these toxicities. Although successful = clinical=20 experience would lead to the conclusion that the role of steroids is = firmly=20 established in the management of brain metastases, even a cursory review = of the=20 literature will demonstrate significant variability in recommendations = and a=20 general lack of well-controlled studies addressing this specific issue. = </P> <DIV class=3DPara> <DIV class=3D"">This systematic review addresses the role of = corticosteroids in=20 the treatment of metastatic brain disease with the following overall = objectives:=20 <TABLE class=3DOrderedList> <TBODY> <TR vAlign=3Dtop> <TD>1. </TD> <TD>To systematically review the evidence available for the = following=20 treatment comparisons for patients diagnosed with brain metastases = specifically addressing the following questions:=20 <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Do steroids improve neurologic symptoms in patients with=20 metastatic brain tumors compared to no treatment?</TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>If steroids are given, what dose should be=20 used?</TD></TR></TBODY></TABLE></TD></TR> <TR vAlign=3Dtop> <TD>2. </TD> <TD>To make recommendations based on this evidence for the role of=20 corticosteroids in the management of these=20 patients.</TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Search strategy</DIV> <P class=3D"">The following electronic databases were searched from 1990 = to=20 September 2008: MEDLINE<SUP>=AE</SUP>, Embase<SUP>=AE</SUP>, Cochrane = Database of=20 Systematic Reviews, Cochrane Controlled Trials Registry, and Cochrane = Database=20 of Abstracts of Reviews of Effects. A broad search strategy using a = combination=20 of subheadings and text words was employed. The search strategy is = documented in=20 the methodology paper for this guideline series by Robinson et al. = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR2">2</A></CITE>].=20 Reference lists of included studies were also reviewed. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Eligibility criteria</DIV> <DIV class=3DPara> <DIV class=3D""> <TABLE class=3DOrderedList border=3D0> <TBODY> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Published in English 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-control studies). = </TD></TR> <TR vAlign=3Dtop> <TD><SPAN style=3D"FONT-SIZE: 1.1em">=95</SPAN> </TD> <TD>Study comparisons include one or more of the=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>steroid therapy versus none.</TD></TR> <TR vAlign=3Dtop> <TD>=96 </TD> <TD>comparison of different doses of steroid=20 therapy.</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 = study arm=20 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 was used = to rate=20 the quality of randomized trials [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR3">3</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR4">4</A></CITE>].=20 The quality of comparative studies using non-randomized designs was = evaluated=20 using eight items selected and modified from existing scales as outlined = in=20 Appendix B of the Methodology chapter in this brain metastases guideline = series=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR2">2</A></CITE>].=20 </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 criteria endorsed by the = American=20 Association of Neurological Surgeons (AANS) and the Congress of = Neurological=20 Surgeons (CNS). These criteria are provided in the methodology paper of = this=20 guideline series. </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Guideline development process</DIV> <P class=3D"">The AANS/CNS convened a multi-disciplinary panel of = clinical experts=20 to develop a series of practice guidelines on the management of brain = metastases=20 based on a systematic review of the literature conducted in = collaboration with=20 methodologists at the McMaster University Evidence-based Practice = Center.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Scientific foundation</DIV> <DIV class=3DPara> <DIV class=3D"">Despite the widespread use of steroids in the management = of brain=20 metastases, only two publications met the stated eligibility criteria = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>].=20 Figure <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Fig1">1</A>=20 outlines the flow of studies through the review process. These two = studies are=20 outlined in the attached evidentiary table. In order to expand the = information=20 base for the =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=94=20 section of this chapter, additional searches were undertaken by = reviewing the=20 bibliographies of these two papers and additional review of the = published=20 literature addressing the treatment of metastatic brain disease for = references=20 to steroid administration. These articles are summarized in the =93<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=94.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_57_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/n11832031700653r/MediaObjects/= 11060_2009_57_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN>Flow of = studies to=20 final number of eligible studies </DIV> <HR> </DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Studies meeting search criteria</DIV> <DIV class=3DPara> <DIV class=3D"">The only two papers that met the search criteria are = summarized=20 below [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>].=20 The details are also summarized in the accompanying evidentiary table=20 (Table <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Tab1">1</A>).=20 In expanding the literature review to seek out additional supporting = information=20 for the "<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>"=20 portion of this document, we did not encounter any additional high = quality=20 studies specifically addressing the role of steroids in brain = metastases. This=20 was in agreement with several previous authors who upon review of the = topic have=20 encountered a lack of detailed, controlled accounts of steroid use in = the=20 studies under review, including the large randomized controlled trials = that=20 often form the basis of treatment decisions and recommendations = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>].<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Summary = of studies=20 meeting the systematic review eligibility criteria </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): Vecht et al. (1994), [<CITE><A=20 = href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 </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""><I>Study design</I> RCT (two trials reported) </P> <P class=3D""><I>Inclusion criteria for both RCTs</I> </P> <P class=3D"">KPS <U><</U> 80, histologically = confirmed=20 diagnosis of solid cancer outside nervous system, together with = single or=20 multiple BM diagnosed by CT </P> <P class=3D""><I>Exclusion criteria for both RCTs</I> </P> <P class=3D"">Age > 75 years; = KPS =3D 90 or 100;=20 prior RT to brain; likelihood of early treatment with = neurosurgery;=20 glucocorticoid administration in the previous 3 months; BM = secondary=20 to lymphoreticular malignancy; diabetes mellitus or disability due = to=20 causes other than BM </P> <P class=3D""><I>Interventions</I> </P> <P class=3D"">First RCT</P> <P class=3D""> G1: dexamethasone 8 mg/day=20 p.o. =D7 7 day (then tapered to discontinue)</P> <P class=3D""> G2: dexamethasone 16 mg/day=20 p.o. =D7 7 day (then tapered to discontinue)</P> <P class=3D"">Second RCT</P> <P class=3D""> After G1 versus G2 not significantly different = at day=20 7</P> <P class=3D""> G3: Dexamethasone 4 mg/day=20 p.o. =D7 28 day (then tapered to discontinue)</P> <P class=3D""> G4: Dexamethasone 16 mg/day=20 p.o. =D7 28 day (then tapered to discontinue)</P> <P class=3D""><I>Notes</I>: all pts scheduled for RT to started at = some=20 point after Day 7 </P> <P class=3D"">(RT dose/schedule not reported); all pts received = ranitidine=20 150 mg bid</P> <P class=3D""><I>Median follow-up</I>: not reported </P> <P class=3D""># <I>male</I>: </P> <P class=3D"">G1: 14/20; G2: 14/22; G3: 12/24; G4: 7/23</P> <P class=3D""><I>Median age (range)</I>: median not reported; mean = age =B1 SD: </P> <P class=3D"">G1: 61 =B1 7.6 years</P> <P class=3D"">G2: 61 =B1 11.5 years</P> <P class=3D"">G3: 60 =B1 9.9 years</P> <P class=3D"">G4: 56 =B1 10.9 years</P> <P class=3D""><I>Predominant tumor types</I>: </P> <P class=3D"">G1: lung 11/20, breast 4/20, gastrointestinal 4/20, = other=20 1/20</P> <P class=3D"">G2: lung 10/22, breast 6/22, kidney 3/22, = gastrointestinal=20 1/22</P> <P class=3D"">G3: lung 10/24, breast 7/24, kidney 3/24, = gastrointestinal=20 1/24</P> <P class=3D"">G4: lung 12/23, breast 5/23, gastrointestinal 2/23, = kidney=20 2/23</P> <P class=3D""># <I>of brain metastases</I>: </P> <P class=3D"">Not reported</P> <P class=3D""><I>Extra-cranial disease</I>: </P> <P class=3D"">Note reported</P> <P class=3D""><I>Baseline functional performance</I>: </P> <P class=3D"">Mean KPS =B1 SD (range)</P> <P class=3D""> G1: 58.5 =B1 11.8 (40=9680)</P> <P class=3D""> G2: 61.4 =B1 9.4 (50=9680)</P> <P class=3D""> G3: 65.0 =B1 10.6 (40=9680)</P> <P class=3D""> G4: 57.8 =B1 14.1(30=9680)</P></TD> <TD align=3Dleft> <P class=3D""><I>Primary outcome</I> </P> <P class=3D"">Change in KPS on day 7 from day 0</P> <P class=3D""><I>First RCT</I> </P> <P class=3D"">Mean (SD) absolute change in KPS at day 7:</P> <P class=3D"">G1: 8.0 =B1 10.1; G2: = 7.3 =B1 14.2=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts with improved KPS on day 7:</P> <P class=3D"">G1: 60%; G2: 54%</P> <P class=3D"">Mean (SD) absolute change in KPS at day 28:</P> <P class=3D"">G1: 6.7 =B1 18.4; G2: = 13.8 =B1 14.5=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts with improved KPS on day 28:</P> <P class=3D"">G1: 53%; G2: 81%</P> <P class=3D""><I>Second RCT</I> </P> <P class=3D"">Mean (SD) absolute change in KPS at day 7:</P> <P class=3D"">G3: 6.7 =B1 11.3; G4: = 9.1 =B1 12.4=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts with improved KPS on day 7:</P> <P class=3D"">G3: 67%; G4: 70%</P> <P class=3D"">Mean change in KPS (SD) at day 28</P> <P class=3D"">G3: 7.1 =B1 18.2; G4: = 5.6 =B1 18.5=20 (<I>P</I> =3D NS) </P> <P class=3D"">% pts improved:</P> <P class=3D"">G3: 62%; G4: 50%</P> <P class=3D""><I>Adverse events: reported combined results</I> = </P> <P class=3D"">Toxic effects more frequent in G2 + G4 = (16 mg)=20 (<I>P</I> < 0.03) </P> <P class=3D"">Incidence of cushingoid facies or ankle edema = increased with=20 duration of treatment (<I>P</I> =3D 0.02 at day 7 and=20 <I>P</I> =3D 0.03 at day 28) and with higher doses of=20 dexamethasone </P> <P class=3D""><I>At day 28</I>: reported combined results from = both RCTs=20 </P> <P class=3D"">Raised glucose:</P> <P class=3D"">G1: 25%; G2/G4: 21%; G3: 18%</P> <P class=3D"">Raised blood pressure:</P> <P class=3D"">G1: 12%; G2/G4: 26%; G3: 45%</P> <P class=3D"">Infectious disease:</P> <P class=3D"">G1: 6%; G2/G4: 9%; G3: 9%</P> <P class=3D"">Gastrointestinal complaints:</P> <P class=3D"">G1: 6%; G2/G4: 24%; G3: 18%</P> <P class=3D"">Mental changes:</P> <P class=3D"">G1: 19%; G2/G4: 21%; G3: 14%</P> <P class=3D"">Ankle edema:</P> <P class=3D"">G1: 13%; G3: 14%; G2/G4: 26%</P> <P class=3D"">Cushingoid facies:</P> <P class=3D"">G1: 69%; G3: 32%; G2/G4: 65%</P> <P class=3D"">Proximal weakness:</P> <P class=3D"">G1: 38%; G3: 14%; G2/G4: 38%</P></TD> <TD align=3Dleft> <P class=3D""><I>AANS/CNS evidence classification: Class 1</I> = </P> <P class=3D""><I>Due to the relatively small size, heterogeneity = in study=20 design and lack of clarity in the statistical presentation and = analysis=20 there are concerns about over generalizing the results and = conclusions of=20 this trial.</I> </P></TD></TR></TBODY></TABLE> <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): Wolfson et al. (1994), = [<CITE><A=20 = href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>]=20 </P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""><I>Study design</I>: prospective randomized phase II = trial=20 [stratified by response to high-dose dexamethasone] </P> <P class=3D""><I>Inclusion criteria</I> </P> <P class=3D"">Measurable BM on CT; histologically confirmed = primary=20 malignancy; granulocyte counts >1,000/mm<SUP>3</SUP> and serum = glucose=20 <300 mg% </P> <P class=3D""><I>Exclusion criteria</I> </P> <P class=3D"">Primary malignancies including lymphomas, germ cell = tumors,=20 primary CNS tumors, SCLC, multiple primaries, and unknown = primaries;=20 resected BMs; illnesses such as active peptic ulcer disease, = uncontrolled=20 diabetes mellitus (serum glucose ≥ 300 mg%), = adrenal=20 insufficiency or being seropositive for HIV </P> <P class=3D"">prior cranial RT; administration of steroid therapy = more than=20 24 h prior to study entry</P> <P class=3D""><I>Interventions</I> </P> <P class=3D"">G1: dexamethasone 24 mg i.v. every 6 h for = 48 h=20 prior to WBRT; then dexamethasone 4 mg p.o. every 6 h = for=20 2 weeks during WBRT</P> <P class=3D"">G2: dexamethasone 24 mg i.v. every 6 h for = 48 h=20 prior to WBRT</P> <P class=3D""><I>Doses</I> </P> <P class=3D"">G1: WBRT: 30 Gy at 3 Gy/fraction</P> <P class=3D"">G2: WBRT: 30 Gy at 3 Gy/fraction</P> <P class=3D""><I>Note</I>: all pts given H-2 blockers during = steroid=20 administration and oral phenytoin for seizure prophylaxis </P> <P class=3D""><I>Median follow-up</I>: not reported </P> <P class=3D""># <I>male</I> </P> <P class=3D"">G1: 2/7; G2: 3/5</P> <P class=3D""><I>Median age (range)</I>: not reported by treatment = group=20 </P> <P class=3D"">Overall median age: 58 years</P> <P class=3D""><I>Tumor type</I> </P> <P class=3D"">G1: NSCLC 5/7, breast 2/7</P> <P class=3D"">G2: NSCLC 3/5, breast 1/5, bladder 1/5</P> <P class=3D""># <I>of brain metastases</I> </P> <P class=3D"">G1: 1 BM 2/7, 2 BM 4/7, >2 BM 1/7</P> <P class=3D"">G2: 1 BM 2/5, 2 BM 1/5, >2 BM 2/5</P> <P class=3D""><I>Extra-cranial disease</I>: Extra-cranial = metastases: </P> <P class=3D"">G1: 5/7; G2: 3/5</P> <P class=3D""><I>Baseline functional performance</I> </P> <P class=3D"">Not reported</P></TD> <TD align=3Dleft> <P class=3D""><I>Primary outcome</I> </P> <P class=3D"">Overall survival</P> <P class=3D""><I>Survival</I> </P> <P class=3D"">Overall median survival: 4 months (no between = group=20 statistical analyses due to limited pt numbers)</P> <P class=3D""><I>Functional performance</I> </P> <P class=3D"">Change in general performance status:</P> <P class=3D"">G1: improved 2/7, deteriorated 1/7, no change = 4/7</P> <P class=3D"">G2: improved 0/5, deteriorated 1/5, no change = 4/5</P> <P class=3D"">Change in neurological function class:</P> <P class=3D"">G1: improved 1/7, deteriorated 1/7, no change = 5/7</P> <P class=3D"">G2: improved 0/5, deteriorated 1/5, no change = 4/5</P> <P class=3D""><I>Cause of death</I> </P> <P class=3D"">Non-specific and not reported by treatment group</P> <P class=3D""><I>Adverse events/other</I> </P> <P class=3D"">Transient hyperglycemia: 1/12</P></TD> <TD align=3Dleft> <P class=3D""><I>AANS/CNS evidence classification</I>: <I>class = 1</I> </P> <P class=3D""><I>Despite this qualifying as class I the small size = and lack=20 of any statistical analysis render this article useless for any=20 recommendations.</I> </P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>Abbreviations</I>: <I>BM</I> brain metastases, = <I>CNS</I>=20 central nervous system, <I>G1</I> Group 1, <I>G2</I> Group 2, <I>G3</I> = Group 3,=20 <I>G4</I> Group 4, <I>KPS</I> Karnofsky performance score, <I>NSCLC</I>=20 non-small cell lung cancer, <I>NR</I> not reported, <I>Pts</I> patients, = <I>RCT</I> randomized control trial, <I>RT</I> radiotherapy, <I>SCLC</I> = small=20 cell lung cancer, <I>SD</I> standard deviation, <I>WBRT</I> whole-brain=20 radiation therapy </DIV></DIV></DIV></DIV></DIV> <P class=3D"">The first of the two studies to meet the search criteria = described a=20 randomized study of 4, 8 and 16 mg/day dosing of dexamethasone and = found no=20 advantage to higher dosing in patients who were not felt to be in = impending=20 danger of cerebral herniation [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>].=20 Vecht et al., published their findings from two consecutively executed=20 double-blind randomized trials in patients with brain metastases and = Karnofsky=20 performance scores (KPS) of 80 or less which were designed to evaluate = the=20 minimum effective dose of oral dexamethasone. Initially a dexamethasone = dosage=20 of 8 mg/day (Group 1) was compared to 16 mg/day (Group 2), = followed by=20 a comparison of 4 mg/day (Group 3) versus 16 mg/day (Group 4). = The=20 outcomes of interest were alteration in KPS and the frequency of side = effects at=20 days 0, 7, 28, and 56. </P> <P class=3D"">In the initial study, although both groups showed an = improvement,=20 there was no significant difference in KPS improvement comparing the = 8-mg group=20 versus the 16-mg group at day 7 (mean 8.0 =B1 10.1 versus = 7.3 =B1 14.2). At the 28 day point, there was a larger = but still=20 non-significant rate of improvement thought to be biased by earlier = steroid=20 tapering in the lower group. </P> <P class=3D"">In the second trial, again both groups showed improvement. = However,=20 no significant difference between the 4- and 16-mg group (comparing=20 6.7 =B1 11.3 points at day 7 and 7.1 =B1 18.2 = points at=20 day 28, versus 9.1 =B1 12.4 and 5.6 =B1 18.5 = points,=20 respectively) could be detected. Side effects (Cushingoid changes and = extremity=20 edema) occurred more frequently in the 16 mg/day versus the = 4 mg/day=20 group at Day 28 (Combined frequency 91% versus 46%,=20 <I>P</I> < 0.03). </P> <P class=3D"">The authors conclude that for the majority of patients, = the lower=20 doses of 4 and 8 mg dexamethasone per day have an equivalent effect = on=20 improving neurologic performance when compared to a dose of = 16 mg/day at 1=20 and 4 weeks of treatment, in moderately symptomatic patients = without signs=20 of impending herniation. A non-significant trend toward improvement at=20 28 days was noted with the higher dosage. The authors postulated = that the=20 early taper in the lower dosage group led to an increase in recurrence = of=20 symptoms that may have increased this apparent effect. The dosing = recommendation=20 from this study resulted in a set 4 mg/day dosage with a dose taper = for=20 28 days in patients with no symptoms of mass effect used for the = second=20 study. </P> <P class=3D"">Side effects appeared to be dose-dependent, occurring more = frequently in patients using 16 mg/day. Therefore, the authors = concluded=20 that steroid related toxicity was increased with the higher daily = dosage.=20 Although the study is double blind and randomized, the relatively small = size,=20 inconsistencies in the design and lack of clarity in the presentation of = the=20 data and analysis are concerns. Nonetheless, this work appears to be the = most=20 detailed and informative available to assist with formulating treatment=20 recommendations. The data, while extremely limited, support a set of = treatment=20 recommendations which follow a general trend toward higher steroid = dosages in=20 symptomatic patients exhibiting greater mass effect symptoms of = increased=20 intracranial pressure, as opposed to lower doses of steroids for = asymptomatic=20 patients. </P> <P class=3D"">Wolfson et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>]=20 prospectively studied 12 patients with histologically confirmed = malignancies and=20 radiographically documented brain metastases and attempted to evaluate = the=20 indications for glucocorticoids. Patients were scored for general = performance=20 status and neurologic function class. All subjects received 24 mg = of=20 intravenous dexamethasone every 6 h for 48 h and after an = assessment,=20 were randomized to receive either 4 mg of oral dexamethasone every = 6 h=20 (Group 1) or no steroids (Group 2) during radiotherapy (30 Gy in = ten=20 fractions). Prior to randomization, five (33%) had a positive response = and eight=20 (67%) had no response to the high dose level. Seven patients were = randomized to=20 continue receiving steroids at the reduced level and five received none = during=20 radiotherapy. The change in general performance status for Group 1 was: = Improved=20 2/7 (29%), deteriorated 1/7 (15%), no change 4/7 (57%). For Group 2, the = change=20 in performance status was: Improved 0/5 (0%), deteriorated 1/5 (20%) and = no=20 change 4/5 (20%). The change in neurological function for Group 1 was: = Improved=20 1/7 (14%), deteriorated 1/7 (14%), no change 5/7 (72%); change in = neurological=20 function for Group 2 was: Improved 0/5 (0%), deteriorated 1/5 (20%), no = change=20 4/5 (80%). No statistical analysis was performed due to the small sample = size.=20 The authors conclude that the specific role of steroids in treating = patients=20 with metastatic carcinoma to the brain remains uncertain and should be = evaluated=20 in a cooperative prospective trial. Due to the small size and lack of = any=20 statistical analysis, it is impossible to reach any conclusion based on = this=20 study; therefore, no recommendations will be made based on this small = trial.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Role of steroids in metastatic brain disease</DIV> <P class=3D"">Given the extremely limited number of studies which = satisfied the=20 conditions of our search criteria, an additional discussion of published = literature on the subject of corticosteroids in metastatic brain disease = is=20 provided to offer a larger context for this topic. While the following = studies=20 were not part of the body of evidence considered in formulating = treatment=20 recommendations in our evidence-based guidelines, they do highlight = areas of=20 interest where clinical trials are still required to answer important=20 steroid-related questions. </P> <P class=3D"">A review of the outcomes in the Radiation Therapy Oncology = Group=20 (RTOG) studies examining various radiotherapeutic regimens for patients = with=20 metastatic brain disease demonstrated a dramatic early improvement in = patients=20 treated concurrently with steroids during the early phases of the trials = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>].=20 However, as the authors note, the administration of steroids was not = well=20 controlled in these studies and was not a primary point of interest so, = although=20 these observations contributed to the overall clinical impression that = steroids=20 were of benefit in the adjuvant treatment of brain metastases, it is = difficult=20 to extrapolate treatment recommendations from these studies. In Borgelt = et al.,=20 this is shown by the fact that symptomatic patients receiving steroids = had a=20 significant improvement in neurological function as opposed to those who = did not=20 receive steroids. None of these studies suggested that the use of = steroids=20 halted time to progression. </P> <P class=3D"">Gaspar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>]=20 published an American College of Radiology (ACR) Committee on = Appropriateness=20 Criteria consensus report following an expert panel review on the=20 pre-irradiation evaluation and management of brain metastases. The = authors cite=20 six articles to support the generation of their expert opinions = [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 They initially note that although clinical experience has established = the=20 effectiveness of corticosteroids in reducing symptoms and radiographic=20 peritumoral edema, controversy remains on the specific indications and = dosage=20 used. They point out that the earliest studies to support steroid use = prior to=20 radiotherapy used radiation dosing schemes that are presently atypical = and that=20 there was evidence that steroids were only indicated when there was a = concern=20 about raised intracranial pressure [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR12">12</A></CITE>].=20 In one study, 27% of patients who received 10 Gy of single fraction = whole=20 brain radiotherapy (WBRT) experienced signs of increased intracranial = pressure=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR12">12</A></CITE>].=20 They also note evidence from one trial indicating that patients who were = moderately symptomatic who received steroid therapy during radiation = experienced=20 a more rapid improvement in their clinical symptoms, although there was = no=20 impact on progression-free or overall survival. This review went onto = outline=20 several papers addressing the acute and chronic side effects and the = studies=20 that address dosing and toxicity [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR6">6</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 </P> <P class=3D"">This consensus review summarizes the authors=92 views on = steroid use=20 for metastatic brain disease by indicating that the patient who shows = evidence=20 of elevated intracranial pressure, but who does not require immediate = surgical=20 attention for either hydrocephalus or impending herniation, should = receive=20 4=966 mg/day of dexamethasone in divided doses and that the routine = use of=20 corticosteroids in patients without neurological symptoms is not = necessary.=20 </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Effect of steroids on radiographic edema</DIV> <P class=3D"">In 1982, Hatam et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR14">14</A></CITE>]=20 prospectively studied the effect of dexamethasone therapy on peritumoral = edema=20 based on computed tomography (CT) describing specifically three cases of = metastatic intracranial disease in which a linear decrease in edema = volume was=20 observed, reducing the measured volume of edema to one-fourth of the = initial=20 volume after 2 weeks of treatment starting with 4 mg four = times daily=20 and tapered to 1 mg/day. The exact time course for the metastatic = patients=20 was not reported separately but the authors did report a substantial = clinical=20 improvement in these patients they felt was associated with the use of=20 dexamethasone. </P> <P class=3D"">Andersen et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR11">11</A></CITE>]=20 published a subsequent report in 1994 that quantified the effect of = steroid=20 therapy over time on peritumoral brain edema in vivo using a magnetic = imaging=20 based technique. Magnetic resonance based assessments of peritumoral = edema were=20 undertaken on 23 brain tumor patients including 13 with brain metastases = at=20 baseline and at Days 1, 3 and 7 after starting steroid therapy. = Intravenous=20 dexamethasone was used at dose of 0.26=960.64 mg/kg (for a = 70 kg patient=20 this range is 20=9645 mg/day). After 7 days of steroid = treatment the=20 total edema area was reduced by 10.3% in the metastatic patients, with = an=20 average reduction in mean volume of 4.6% after 24 h of treatment = and 13.5%=20 after 7 days. This effect was observed for up to 63 days and = it was=20 demonstrated that after 40=9663 days (6=969 weeks) of steroid = therapy the=20 peritumoral water content was close to the upper normal range for white = matter.=20 The authors concluded that steroids significantly reduce the volume of=20 peritumoral edema in patients with metastatic brain disease even after a = few=20 days of treatment. They postulate a mechanism of steroid-induced = reduction in=20 edema below the level of absorption and commented that they thought they = may=20 have obtained the same effects with a dose-reduction to minimize = potential side=20 effects. </P> <P class=3D"">Minamikawa et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR15">15</A></CITE>]=20 studied the effect of glucocorticoid treatment (methylprednisolone, dose = not=20 specified) on the apparent diffusion coefficient (ADC) imaging in a = series of 13=20 patient including four with metastatic brain disease. Although it is not = possible to examine the effects on the metastatic patients separately, = the=20 authors suggested that ADC imaging was a more sensitive technique than=20 conventional MRI imaging for studying the effects of steroids on = peritumoral=20 edema, even in the absence of detectable MRI changes. </P></DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>Dosing and toxicity</DIV> <P class=3D"">Hempen et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>]=20 retrospectively reviewed 138 consecutive patients to evaluate the impact = of=20 dosage and duration of dexamethasone administration during radiation = therapy for=20 patients with both primary and metastatic brain tumors = (n =3D 91). The=20 dosage of dexamethasone was gradually reduced from an initial median = dose of=20 7=9612 mg/day to a median of 1=966 mg/day with an average = duration of=20 7 weeks for the metastatic group. The authors reported a period of = initial=20 clinical improvement with relatively few side effects. Specifically, 33% = of=20 patients reported improvement in symptoms with steroid use prior to=20 radiotherapy, 44% during radiotherapy and 11% following radiotherapy. = However,=20 as dexamethasone was continued, this trend reversed and less symptom = relief was=20 observed with increasing toxicity. Life-threatening complications were = rare.=20 Side effects attributed to steroid use included: hyperglycemia (47%), = peripheral=20 edema (11%), psychiatric disorder (10%), candidiasis (7%), Cushing=92s = syndrome=20 (4%), muscular weakness (4%) and pulmonary embolus (2%). Of a cohort of = 13=20 clinically asymptomatic patients who received no dexamethasone during=20 radiotherapy, 12 (92%) showed no sign of worsening neurological = problems. The=20 patient with worsened symptoms had brain stem involvement. The authors = conclude=20 that dexamethasone effectively minimizes neurological symptoms and = radiation=20 therapy related side effects in patients with both primary and secondary = brain=20 tumors. The toxicity of dexamethasone was noted to increase over time = and=20 therefore a patient-specific dosing pattern and taper was recommended. = The=20 authors suggested that a prospective study specifically addressing the = relative=20 balance of symptom relief versus toxicity would be of benefit and that = there is=20 little evidence to support the use of steroids in the asymptomatic = patient. </P> <P class=3D"">In 1999, Lagerwaard et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR8">8</A></CITE>]=20 published an extensive retrospective review of 1,292 patients with = metastatic=20 brain disease referred to a single institution to identify prognostic = (risk)=20 factors. The majority of patients were treated with WBRT = (n =3D 1,079,=20 84%); 118 (9%) were treated with steroids only and 95 (7%) with surgery = and=20 radiotherapy. Data obtained included: age, sex, performance status, = number and=20 distribution of brain metastases, site of primary tumor, histology, = interval=20 between primary tumor and brain metastases, systemic tumor activity, = serum=20 lactate dehydrogenase, response to steroid treatment, and treatment = modality.=20 Dexamethasone was used in a dose range of 4=9616 mg/day (mean = dosage=20 14.6 mg/day), which was =93tapered slowly and discontinued in the = weeks=20 following therapy=94 (specific details not stated). </P> <P class=3D"">Response to steroid therapy was judged retrospectively, = from review=20 of the medical records, as good (marked improvement), moderate (some=20 improvement) or little (little or no improvement). Both univariate and=20 multivariate analyses were performed. The overall median survival was=20 3.4 months, with 6 month, 1, and 2 year survival = percentages of=20 36, 12, and 4%, respectively. Median survival was 1.3 months in = patients=20 treated with steroids only, 3.6 months in patients treated with=20 radiotherapy, and 8.9 months in patients treated with surgical = resection=20 followed by radiotherapy (all comparisons = <I>P</I> < 0.0001). </P> <P class=3D"">Multivariate analysis confirmed the previously reported = observation=20 that the impact of treatment modality on survival in patients with brain = metastases was the most significant single factor in predicting = survival.=20 However, response to steroid treatment, performance status, systemic = tumor=20 activity and serum lactate dehydrogenase levels were also all = independent=20 prognostic factors on survival, second only to treatment modality in = level of=20 significance. Site of primary tumor, age, and number of brain metastases = were=20 also identified as prognostic factors. </P> <P class=3D"">The authors concluded that the strongest prognostic (risk) = factors=20 were choice of treatment modality, response to steroids, performance = status, and=20 evidence of systemic disease and they proposed using these classifiers = in=20 identifying favorable and unfavorable subgroups of patients with brain=20 metastases for future studies. </P> <P class=3D"">Millar et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>]=20 attempted to assess the impact of steroid therapy in the management of = brain=20 metastases by undertaking a systematic review of published randomized = trials on=20 WBRT for multiple cerebral metastases. In this extensive review = published in=20 2004, the authors identified 21 full manuscripts of published randomized = controlled trials involving WBRT in the treatment of multiple brain = metastases=20 from 1971 to 2003. They attempted to extract details on the use and type = of=20 steroid, timing of steroids relative to radiotherapy, response = assessment and=20 contribution of steroids to overall outcome. They reported that 18 of = the 21=20 trials reviewed documented steroid use. Overall survival was an outcome = assessed=20 in all studies. Thirteen studies assessed neurological response and ten = assessed=20 a radiographic endpoint. Ten of the studies (48%) suggested a positive = effect of=20 steroid use on the outcome assessed. Only one study=97in the palliative=20 setting=97provided a fixed steroid dose. </P> <P class=3D"">The authors concluded that the reporting of steroid use in = previously published randomized trials assessing treatment for patients = with=20 brain metastases is =93non-uniform and not sufficiently detailed=94 = making it=20 difficult to assess the treatment effect. They call for a more standard = approach=20 to steroid dose in future studies or at a minimum better reporting of = dosages=20 used to better determine symptom response and durability of response. = They also=20 note that side effects of steroid use and the ability to taper off = steroids=20 after treatment intervention are additional outcomes of interest in the = planning=20 of future studies. </P> <P class=3D"">Weissman et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR16">16</A></CITE>]=20 published their experience with a treatment regimen designed to reduce = steroid=20 toxicity in 20 patients with newly diagnosed brain metastases. All = patients=20 received dexamethasone starting at 8 mg twice daily for 4 days = then=20 4 mg twice daily for 4 days followed by 2 mg twice daily = until=20 the last day of radiation therapy. Radiation dose and schedules ranged = from=20 20 Gy in five fractions to 58 Gy in 29 fractions. Fourteen = patients=20 (70%) received dexamethasone for a minimum of 24 h before their = first=20 radiation treatment and seven of those patients (50%) experienced = improvement in=20 neurologic symptoms and signs before radiotherapy. Fourteen patients = (70%)=20 completed the entire course of radiation and dexamethasone as planned. = One=20 patient required reinstitution of dexamethasone within 30 days of = finishing=20 radiation for neurological decline. The authors felt that the = twice-daily dose=20 was well tolerated. Steroid related toxicity included hyperglycemia = (5%),=20 candida esophagitis (5%), steroid pseudorheumatism (10%), peripheral = edema (5%)=20 and steroid withdrawal syndrome (5%). </P> <P class=3D"">In 2006, the results of a series of systematic reviews = with the=20 stated purpose =93to establish evidence-based guidelines and identify=20 controversies regarding the management of patients with brain = metastases=94 was=20 published by Soffietti et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>].=20 This was conducted by a multi-disciplinary task force of the European = Federation=20 of Neurological Societies and includes a review of data obtained from = the=20 Cochrane Library, bibliographic databases, overview papers and previous=20 guidelines from scientific societies and organizations. Under the = section on=20 supportive care and steroids only one original article is cited and = reviewed,=20 and that is the publication by Vecht [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>],=20 which also met the eligibility criteria for this guideline paper and is=20 discussed extensively in the scientific foundation section. This paper = was used=20 to support the recommendation that, in most cases, initial dexamethasone = doses=20 should not exceed 4=968 mg/day. However, in patients with more = severe=20 symptoms related to increased intracranial pressure doses of = 16 mg/day or=20 higher should be considered (Level of Evidence B) [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR17">17</A></CITE>].=20 The remainder of the recommendations were based on uniform consensus of = the task=20 force (referred to as a =93Good Practice Point=94) and are summarized = below.=20 Dexamethasone was noted as the corticosteroid of choice and twice daily = dosing=20 was thought to be sufficient (Good Practice Point). Tapering of steroid = dosing=20 within 1 week of starting therapy and discontinuation within = 2 weeks=20 if possible was encouraged (Good Practice Point). Finally, patients who = do not=20 have signs or symptoms of increased intracranial pressure do not have to = be=20 treated with steroids (Good Practice Point). </P> <P class=3D"">Given the very limited number of studies that met the = inclusion=20 criteria for the systematic literature review on the role of steroids in = metastatic brain disease, we are unable to propose specific guidelines = on many=20 of the issues of central interest to the treating physician. </P> <P class=3D"">In summarizing the <A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>=20 section above we are able to offer the following observations: first, = Overall=20 the literature favors the position that corticosteroids are of benefit = in=20 providing temporary symptomatic relief of CNS symptoms related to = increased=20 intracranial pressure and edema secondary to brain metastases [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 Secondly, dexamethasone is the steroid most often used, with the = rationale that=20 it has limited mineralocorticoid effects. Other steroids have been used = with=20 similar reported clinical responses. Dosing has been recommended to be=20 sufficient at twice daily although more frequent dosing has been = suggested with=20 increasing concern for raised intracranial pressure and impending = herniation=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR14">14</A></CITE>].=20 Finally, based primarily on the asymptomatic patients in the study by = Hempen et=20 al., it is the opinion offered in the available studies that = asymptomatic=20 patients do not require steroids [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>].=20 Numerous authors cite concerns for the toxicity of steroid therapy and = due to=20 the lack of a uniform recommendation on dosing and the apparent = complexity of=20 the response in individual patients it has been recommended that dose = reduction=20 be considered within 1 week of initiation of treatment. The dose = reduction=20 appears to often require alteration in individual patients due to the = diversity=20 of response [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR13">13</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR16">16</A></CITE>].=20 </P> <P class=3D"">An interesting observation in the review of the literature = on this=20 subject is the number of authors who appear to assume that steroids are = a=20 mainstay of treatment for the patient with metastatic brain disease = despite the=20 relative lack of detailed information available to guide specific = therapy. In=20 general, the evidence for specific dosages and regimens of steroids are = poorly=20 detailed. On the other hand, there is very little information provided = in the=20 literature that suggests that steroids are of no benefit in this patient = population with the exception of the asymptomatic patient. </P> <P class=3D"">Given the general consensus in the literature that = steroids are of=20 benefit in selected patients with metastatic brain disease and the = frequent=20 observation that dosing needs to be specifically tailored to the = individual, it=20 appears unlikely that in depth studies specifically addressing this = issue will=20 be forthcoming. However, the need for additional recommendations for = dosing and=20 duration of therapy may result in an increased awareness of this concern = and=20 potentially an alteration of clinical trials designed to address = comparisons.=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Summary and conclusions</DIV> <P class=3D"">In terms of articles meeting the search criteria described = in the=20 methods section above, the study by Vecht et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 stands alone in providing the most convincing data on the role for = steroids in=20 patients with brain metastases and for the choice of dosing. Based on = their=20 observations of improvement in all groups treated with steroids, a level = 3=20 recommendation can be made as follows: </P> <DIV class=3D""><A name=3DSec15></A> <DIV class=3DHeading3>Steroid therapy versus no therapy</DIV> <P class=3D"">Corticosteroids are recommended to provide temporary = symptomatic=20 relief of CNS symptoms related to increased intracranial pressure and = edema=20 secondary to brain metastases. (Level 3 recommendation). Dexamethasone = is the=20 corticosteroid of choice, mainly because of its limited = mineralocorticoid=20 effects, and should be tapered slowly over several weeks to avoid = rebound=20 symptoms. </P> <P class=3D"">The Vecht et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 article provides evidence that the administration of steroids provides = relief of=20 symptoms in patients with symptomatic brain metastatic disease; however, = recognizing that there is no control group (a =93no treatment group=94) = only the=20 lowest grade of recommendation can be made. </P> <P class=3D"">Vecht et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR5">5</A></CITE>]=20 also conclude that a starting dose of 4=968 mg/day be considered, = unless=20 patients exhibit severe symptoms consistent with increased intracranial=20 pressure. They further recommended that those patients at high risk for = severe=20 consequences from raised intracranial pressure be considered for more = aggressive=20 dosing on the order of doses of 16 mg/day or higher. This study is = relied=20 upon heavily in the systematic review and consensus reports summarized = in the=20 "<A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#Sec10">Discussion</A>"=20 section above [<CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR1">1</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/n11832031700653r/fulltext.htm= l#CR9">9</A></CITE>].=20 However, the number of patients involved is relatively small and the = study lacks=20 a validation group; thus, despite the randomized design and ranking = yielding a=20 higher class of evidence, the recommendation itself is downgraded to = reflect=20 these concerns. Based on this study design and results, the following=20 recommendation can be made. </P></DIV> <DIV class=3D""><A name=3DSec16></A> <DIV class=3DHeading3>Comparison of different doses of steroid = therapy</DIV> <P class=3D"">It is recommended for patients who are symptomatic from = metastatic=20 brain disease that a starting dose of 4=968 mg/day of dexamethasone = be=20 considered, unless patients exhibit severe symptoms consistent with = increased=20 intracranial pressure. In these patients it is recommended that higher = doses=20 such as 16 mg/day or more be considered. (Level 3 recommendation)=20 </P></DIV></DIV> <DIV class=3D""><A name=3DSec17></A> <HR> <DIV class=3Dheading2>Key issues for further investigation</DIV> <DIV class=3DPara> <DIV class=3D"">Given the number of patients who receive steroids as a = portion of=20 their care for treating the signs and symptoms of brain metastases, the = medical=20 literature contains relatively few detailed reports specifically = addressing this=20 issue. It may be that the early observation that there was little effect = on=20 overall survival has limited the subsequent level of interest in this = issue.=20 Review of the literature finds that the majority of authors on the = subject feel=20 that there is a symptomatic benefit from the use of systemic steroids in = the=20 management of these patients. It is not clear that there is an urgent = need for=20 randomized trials specifically addressing the issue of steroid dosing = and=20 toxicity. However, future studies could be planned to allow better = control,=20 recording and analysis of steroid dosing and response to allow a more = robust=20 analysis of the risk to benefit ratio of various dosing regimens. This = would=20 potentially optimize the benefits while limiting the side effects, which = could=20 lead to an improvement in overall outcome in addition to improving = quality of=20 life measures in the short term.=20 <BLOCKQUOTE> <P class=3D""><I>No ongoing or recently closed clinical trials on the = use of=20 steroids for the management of brain metastases were found that met = the=20 eligibility criteria.</I> </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>Reference </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Soffietti R, Cornu P, Delattre JY, Grant R, = Graus F,=20 Grisold W et al (2006) EFNS guidelines on diagnosis and treatment = of brain=20 metastases: report of an EFNS task force. 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