10.1007/s11060-009-0032-0</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 6.00.6000.16915" 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 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0032-0</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Primary CNS lymphoma in the = elderly:=20 temozolomide therapy and MGMT status </DIV> <P class=3DAuthorGroup>Delia Kurzwelly<SUP>1</SUP>,=20 Martin Glas<SUP>1</SUP>, Patrick Roth<SUP>2</SUP>,=20 Elke Weimann<SUP>3</SUP>, Hanns Lohner<SUP>4</SUP>,=20 Andreas Waha<SUP>5</SUP>, Martin Schabet<SUP>3</SUP>,=20 Guido Reifenberger<SUP>6</SUP>, Michael Weller<SUP>2</SUP> and = Ulrich Herrlinger<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#ContactOfAuthor10"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/01873364r8l55334/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>Division of Clinical Neurooncology, = Department=20 of Neurology, University of Bonn, Sigmund-Freud-Str. 25, = 53105 Bonn,=20 Germany</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, University of = Zurich,=20 Frauenklinikstr. 26, Zurich, CH, 8091,=20 Switzerland</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Klinikum = Ludwigsburg,=20 Posilipostr. 4, 71640 Ludwigsburg, = Germany</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 Neurology, Klinikum = Rosenheim,=20 Pettenkoferstr. 10, 83022 Rosenheim,=20 Germany</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 Neuropathology, = University of=20 Bonn, Sigmund-Freud-Str. 25, 53105 Bonn,=20 Germany</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 Neuropathology, Heinrich = Heine=20 University Duesseldorf, Universit=E4tsstr. 1, = 40225 Duesseldorf,=20 Germany</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor10></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/01873364r8l55334/contact.gif" = border=3D0></TD> = <TD><STRONG>Ulrich </STRONG><STRONG>Herrlinger</STRONG><STRONG></STR= ONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:ulrich.herrlinger@ukb.uni-bonn.de">ulrich.herrlinger@ukb.u= ni-bonn.de</A></TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>15 July 2009 <STRONG>Accepted:=20 </STRONG>30 September 2009 <STRONG>Published = online:=20 </STRONG>20 October 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>This retrospective = series=20 explores temozolomide monotherapy in elderly patients with primary CNS = lymphoma=20 (PCNSL) and severe comorbidities. In 17 patients (62=9690 years = old), the=20 complete response rate was 47%, median progression-free survival was=20 5 months, and median overall survival was 21 months. Five of = 17=20 patients (29.4%) had prolonged responses for at least 12 months and = survived for more than 24 months. Three of these patients had a = methylated=20 O<SUP>6</SUP>-methylguanine-DNA methyltransferase (MGMT) promoter, while = the=20 MGMT status was not assessable in the remaining two patients. = Temozolomide=20 monotherapy appears to be effective in a subgroup of elderly PCNSL = patients and=20 deserves further evaluation. </DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Primary=20 central nervous system=20 lymphoma - Chemotherapy - Temozolomide - MG= MT </P> <DIV class=3DArticleNote><SPAN class=3D"">Delia Kurzwelly and Martin = Glas=20 contributed equally.</SPAN></DIV> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">High-dose methotrexate (HD-MTX)-based chemotherapy is the = standard=20 therapy for patients with primary CNS lymphoma (PCNSL). This treatment = can also=20 be applied to elderly patients without substantial toxicity as long as = organ=20 functions, especially renal function, are adequate [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR1">1</A></CITE>].=20 Some elderly patients, however, cannot receive HD-MTX because of more = markedly=20 impaired renal function (creatinin = clearance < 50 ml/min) or=20 other comorbidities. No standard of care has been defined for this group = of=20 patients. Whole brain radiotherapy (WBRT) may not be appropriate because = of the=20 increased risk of late neurotoxicity in the elderly and its overall = limited=20 efficacy with a median survival time of 12 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR2">2</A></CITE>].=20 This warrants the search for new chemotherapy regimens for these = patients. The=20 alkylating agent temozolomide (TMZ) penetrates into the brain well and = has shown=20 some efficacy in the second-line therapy of PCNSL [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR5">5</A></CITE>];=20 furthermore, it is likely to be tolerated better than HD-MTX in patients = with=20 comorbidities. Thus, TMZ may be a promising treatment for elderly = patients with=20 PCNSL who cannot receive HD-MTX. As O<SUP>6</SUP>-methylguanine-DNA=20 methyltransferase (MGMT) gene promoter methylation is highly predictive = for=20 survival in TMZ-treated glioblastoma patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR6">6</A></CITE>],=20 we also determined the MGMT promoter methylation status in the majority = of our=20 patients. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <P class=3D"">We reviewed the charts of four German medical centers to = identify=20 PCNSL patients treated with primary TMZ chemotherapy, and analyzed = toxicity,=20 response to therapy and survival parameters in these patients. The best = response=20 to therapy was assessed in the absence of steroids by contrast-enhanced = MRI=20 according to the criteria established by Macdonald et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR7">7</A></CITE>].=20 Toxicity was graded according to the World Health Organization = classification.=20 </P> <P class=3D"">For the analysis of the MGMT promoter methylation status, = genomic=20 DNA was extracted from formalin-fixed paraffin-embedded tumor samples = and=20 subjected to bisulfite conversion using the EZ DNA Methylation-Gold=20 Kit<SUP>=99</SUP> (HISS Diagnostics, Freiburg, Germany) or the EpiTect = Bisulfite=20 Kit (Qiagen, Hilden, Germany). Bisulfite converted DNA was then analyzed = by the=20 authors using methylation-specific PCR (MSP) [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR8">8</A></CITE>]=20 or direct pyrosequencing [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR9">9</A></CITE>]=20 in all patients with a sufficient amount of paraffin-embedded tumor = tissue=20 available (for detailed descriptions of the methylation assays, see = [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR9">9</A></CITE>]).=20 </P></DIV> <DIV class=3D""><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3DPara> <DIV class=3D"">Seventeen patients with histologically proven PCNSL and = a median=20 age of 75 years (range 62=9690 years; Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>)=20 who received first-line therapy with TMZ = (100=96200 mg/m<SUP>2</SUP> on days=20 1=965 of a 28-day cycle) were identified. Two of the 17 patients have = been=20 previously reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR10">10</A></CITE>].=20 HD-MTX therapy was regarded inappropriate because of impaired renal = function=20 (patients 3, 4, 6, 12 of Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>),=20 high age (patients 5, 7, 9, 11, 13=9617), problems with fluid and = electrolyte=20 balance due to a syndrome of inadequate antidiuretic hormone secretion = (SIADH;=20 patient 1), extensive edema (patient 2), severe cardiovascular disease = (patient=20 10), or non-compliance due to oligophrenia (patient 8). The median = number of TMZ=20 cycles applied was three (range 1=968 cycles).<A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Patient=20 characteristics, treatment outcome and MGMT promoter methylation status = of=20 patients with primary central nervous system lymphoma treated with = first-line=20 temozolomide (TMZ) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Patient no.</P></TH> <TH align=3Dleft> <P class=3D"">Age at diagnosis (years), gender</P></TH> <TH align=3Dleft> <P class=3D"">Dose (mg/m<SUP>2</SUP>/d), No. of TMZ = cycles<SUP>a</SUP>=20 </P></TH> <TH align=3Dleft> <P class=3D"">Response to TMZ<SUP>b</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">PFS (months)</P></TH> <TH align=3Dleft> <P class=3D"">Further therapy at relapse (response)</P></TH> <TH align=3Dleft> <P class=3D"">OS (months)</P></TH> <TH align=3Dleft> <P class=3D"">MGMT status</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">63, m</P></TD> <TD align=3Dleft> <P class=3D"">200, 8 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">72+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">72+</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">75, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 4 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">7 =D7 TMZ (PR) and WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">78, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD> <TD align=3Dleft> <P class=3D"">1 =D7 PCV (NA), WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">33</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">4</P></TD> <TD align=3Dleft> <P class=3D"">72, f</P></TD> <TD align=3Dleft> <P class=3D"">150, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">72, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">WBRT (NA)</P></TD> <TD align=3Dleft> <P class=3D"">8</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">6</P></TD> <TD align=3Dleft> <P class=3D"">77, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">7</P></TD> <TD align=3Dleft> <P class=3D"">90, f</P></TD> <TD align=3Dleft> <P class=3D"">100, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">7</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">8</P></TD> <TD align=3Dleft> <P class=3D"">62, m</P></TD> <TD align=3Dleft> <P class=3D"">200, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">3 =D7 TMZ (PD), PCV (NA)</P></TD> <TD align=3Dleft> <P class=3D"">9</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">9</P></TD> <TD align=3Dleft> <P class=3D"">88, f</P></TD> <TD align=3Dleft> <P class=3D"">100, 4 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">4</P></TD> <TD align=3Dleft> <P class=3D"">Rituximab (NA)</P></TD> <TD align=3Dleft> <P class=3D"">5+</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">10</P></TD> <TD align=3Dleft> <P class=3D"">73, m</P></TD> <TD align=3Dleft> <P class=3D"">200, 2 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">24+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">24+</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">11</P></TD> <TD align=3Dleft> <P class=3D"">82, f</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">12</P></TD> <TD align=3Dleft> <P class=3D"">67, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 2 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">16+</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">13</P></TD> <TD align=3Dleft> <P class=3D"">81, m</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">14</P></TD> <TD align=3Dleft> <P class=3D"">75, f</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">15</P></TD> <TD align=3Dleft> <P class=3D"">74, m</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">26+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">26+</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">16</P></TD> <TD align=3Dleft> <P class=3D"">85, m</P></TD> <TD align=3Dleft> <P class=3D"">150, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">17</P></TD> <TD align=3Dleft> <P class=3D"">80, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 8 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">29+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">29+</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>m</I> male, <I>f</I> female, <I>NA</I> not = assessable,=20 <I>PFS</I> progression-free survival, <I>OS</I> overall survival, = <I>CR</I>=20 complete response, <I>PR</I> partial response, <I>PD</I> progressive = disease,=20 <I>TMZ</I> temozolomide; <I>PCV</I> procarbazine, <I>CCNU</I> = vincristine,=20 <I>WBRT</I> whole brain radiotherapy (39.6=9645 Gy), <I>MGMT</I>=20 O<SUP>6</SUP>-methylguanine-DNA methyltransferase, + methylated MGMT = promoter; −=20 non-methylated MGMT promoter </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>All patients received standard TMZ treatment = (days 1=20 to 5 out of a 28-day cycle) </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>b</SUP>All patients were off steroids at the time = of response=20 evaluation </DIV></DIV></DIV></DIV></DIV> <P class=3D"">Two patients (12%) developed WHO high-grade hematoxicity: = patient 3=20 had grade 4 leukopenia and thrombocytopenia with subsequent severe = infection;=20 patient 4 had grade 4 leukopenia and grade 3 thrombopenia. One patient = (no. 8)=20 developed grade 1 skin erythema, which might possibly be associated with = TMZ=20 therapy. One patient (no. 15) had to discontinue treatment due to=20 spondylodiscitis, and another patient (no. 5) had grade 2 colitis with = an=20 unclear causal association to TMZ therapy. </P> <DIV class=3DPara> <DIV class=3D"">Eight patients (47%) had a complete response (CR), one = patient had=20 a partial response (PR), and another eight patients had progressive = disease (PD)=20 (Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>).=20 The median progression-free survival (mPFS) was 5 months (range = 1=9672+=20 months; Fig. <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Fig1">1</A>a).=20 Five of 17 patients (29.4%) had prolonged responses for more than=20 12 months. The median overall survival (mOS) was 21 months = (range=20 1=9672+ months; Fig. <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Fig1">1</A>b).=20 The estimated 2-year survival rate was 39.7%. Second- and third-line = therapies=20 are listed in Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>.=20 In four patients (patients 2, 4, 5, and 12), progression-free survival = (PFS)=20 after second-line WBRT was longer than PFS after primary TMZ = chemotherapy.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_32_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/01873364r8l55334/MediaObjects/= 11060_2009_32_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Kaplan=96Meier=20 estimates are shown for <B>a</B> progression-free survival (median,=20 5 months) and <B>b</B> overall survival (median, 21 months) in = 17=20 elderly patients with primary central nervous system lymphoma treated = with=20 first-line TMZ chemotherapy </DIV> <HR> </DIV></DIV> <P class=3D"">Tumor specimens of ten patients were available for MGMT = analysis.=20 MGMT promoter methylation (mMGMT; Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>)=20 in the tumor tissue was found in six patients, while four patients had a = non-methylated MGMT promoter (nmMGMT). Overall survival was 21+ months = in the=20 group of mMGMT patients, whereas mOS was 9 months in the group of = nmMGMT=20 patients. Furthermore, mPFS was 5+ months in mMGMT patients and = 3 months in=20 nmMGMT patients. Of note, three of the five patients surviving for=20 24 months or more had a methylated MGMT promoter, while MGMT was = not=20 assessable in two of these patients. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">First-line chemotherapy with TMZ shows good tolerability = and some=20 activity in elderly PCNSL patients. CR rate (47%), mPFS (5 months) = and mOS=20 (21 months) compare well to presumably more toxic regimens such as=20 chemotherapy on a HD-MTX, lomustine and procarbazine base (CR rate = 42=9647%, mPFS=20 5.9=966.8 months and mOS 14.3=9615.4 months) [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR12">12</A></CITE>].=20 Survival with TMZ monotherapy is somewhat shorter than with a = combination of=20 HD-MTX and TMZ (CR 55%, mPFS 8 months, mOS 35 months) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR13">13</A></CITE>].=20 However, it is possible that selection bias negatively impacted survival = data in=20 our study because many older patients with severe comorbidities = participated in=20 the study. </P> <P class=3D"">Similar to what has been shown for the combination of=20 HD-MTX/lomustine/procarbazine [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR12">12</A></CITE>],=20 our patient population falls into two subgroups: (1) the larger group of = patients not responding at all to chemotherapy or rapidly progressing = after a=20 very short period of response and (2) the smaller group of patients = deriving=20 notable benefit from chemotherapy with extended PFS and a high potential = for=20 long-term survival (4 of 17 patients surviving relapse-free for = substantially=20 more than 2 years). Our MGMT promoter methylation data are = compatible with=20 the notion that sustained response and prolonged survival are not = possible in=20 the presence of a non-methylated MGMT promoter (PFS 1=963 months). = Since none=20 of the patients surviving more than 24 months had a non-methylated = MGMT=20 promoter, it may be speculated that a methylated MGMT promoter is a = necessary=20 prerequisite for a sustained response. However, a methylated MGMT = promoter=20 cannot be the only molecular factor influencing response and survival = since=20 three of our patients with a methylated MGMT promoter nevertheless had a = short=20 PFS of less than 5 months. Certainly, our limited MGMT data do not=20 sufficiently substantiate this hypothesis, which has to be further = explored in=20 trials that apply alkylating agents to patients with PCNSL. Only larger = trials=20 will then allow statistical comparison of survival parameters between = mMGMT and=20 nmMGMT patients. Of note, salvage WBRT was an effective therapy in four = of five=20 patients. </P> <P class=3D"">The treatment of elderly patients with PCNSL remains a = challenge.=20 According to our preliminary data, TMZ therapy may be an option for some = of=20 these patients. 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From: Subject: 10.1007/s11060-009-0032-0 Date: Tue, 27 Oct 2009 11:17:14 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_003D_01CA56F7.09430B20" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_003D_01CA56F7.09430B20 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/01873364r8l55334/fulltext.html 10.1007/s11060-009-0032-0</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 6.00.6000.16915" 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 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0032-0</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Primary CNS lymphoma in the = elderly:=20 temozolomide therapy and MGMT status </DIV> <P class=3DAuthorGroup>Delia Kurzwelly<SUP>1</SUP>,=20 Martin Glas<SUP>1</SUP>, Patrick Roth<SUP>2</SUP>,=20 Elke Weimann<SUP>3</SUP>, Hanns Lohner<SUP>4</SUP>,=20 Andreas Waha<SUP>5</SUP>, Martin Schabet<SUP>3</SUP>,=20 Guido Reifenberger<SUP>6</SUP>, Michael Weller<SUP>2</SUP> and = Ulrich Herrlinger<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#ContactOfAuthor10"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/01873364r8l55334/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>Division of Clinical Neurooncology, = Department=20 of Neurology, University of Bonn, Sigmund-Freud-Str. 25, = 53105 Bonn,=20 Germany</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, University of = Zurich,=20 Frauenklinikstr. 26, Zurich, CH, 8091,=20 Switzerland</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Department of Neurology, Klinikum = Ludwigsburg,=20 Posilipostr. 4, 71640 Ludwigsburg, = Germany</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 Neurology, Klinikum = Rosenheim,=20 Pettenkoferstr. 10, 83022 Rosenheim,=20 Germany</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 Neuropathology, = University of=20 Bonn, Sigmund-Freud-Str. 25, 53105 Bonn,=20 Germany</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 Neuropathology, Heinrich = Heine=20 University Duesseldorf, Universit=E4tsstr. 1, = 40225 Duesseldorf,=20 Germany</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor10></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/01873364r8l55334/contact.gif" = border=3D0></TD> = <TD><STRONG>Ulrich </STRONG><STRONG>Herrlinger</STRONG><STRONG></STR= ONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:ulrich.herrlinger@ukb.uni-bonn.de">ulrich.herrlinger@ukb.u= ni-bonn.de</A></TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>15 July 2009 <STRONG>Accepted:=20 </STRONG>30 September 2009 <STRONG>Published = online:=20 </STRONG>20 October 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>This retrospective = series=20 explores temozolomide monotherapy in elderly patients with primary CNS = lymphoma=20 (PCNSL) and severe comorbidities. In 17 patients (62=9690 years = old), the=20 complete response rate was 47%, median progression-free survival was=20 5 months, and median overall survival was 21 months. Five of = 17=20 patients (29.4%) had prolonged responses for at least 12 months and = survived for more than 24 months. Three of these patients had a = methylated=20 O<SUP>6</SUP>-methylguanine-DNA methyltransferase (MGMT) promoter, while = the=20 MGMT status was not assessable in the remaining two patients. = Temozolomide=20 monotherapy appears to be effective in a subgroup of elderly PCNSL = patients and=20 deserves further evaluation. </DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>Primary=20 central nervous system=20 lymphoma - Chemotherapy - Temozolomide - MG= MT </P> <DIV class=3DArticleNote><SPAN class=3D"">Delia Kurzwelly and Martin = Glas=20 contributed equally.</SPAN></DIV> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">High-dose methotrexate (HD-MTX)-based chemotherapy is the = standard=20 therapy for patients with primary CNS lymphoma (PCNSL). This treatment = can also=20 be applied to elderly patients without substantial toxicity as long as = organ=20 functions, especially renal function, are adequate [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR1">1</A></CITE>].=20 Some elderly patients, however, cannot receive HD-MTX because of more = markedly=20 impaired renal function (creatinin = clearance < 50 ml/min) or=20 other comorbidities. No standard of care has been defined for this group = of=20 patients. Whole brain radiotherapy (WBRT) may not be appropriate because = of the=20 increased risk of late neurotoxicity in the elderly and its overall = limited=20 efficacy with a median survival time of 12 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR2">2</A></CITE>].=20 This warrants the search for new chemotherapy regimens for these = patients. The=20 alkylating agent temozolomide (TMZ) penetrates into the brain well and = has shown=20 some efficacy in the second-line therapy of PCNSL [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR3">3</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR5">5</A></CITE>];=20 furthermore, it is likely to be tolerated better than HD-MTX in patients = with=20 comorbidities. Thus, TMZ may be a promising treatment for elderly = patients with=20 PCNSL who cannot receive HD-MTX. As O<SUP>6</SUP>-methylguanine-DNA=20 methyltransferase (MGMT) gene promoter methylation is highly predictive = for=20 survival in TMZ-treated glioblastoma patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR6">6</A></CITE>],=20 we also determined the MGMT promoter methylation status in the majority = of our=20 patients. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <P class=3D"">We reviewed the charts of four German medical centers to = identify=20 PCNSL patients treated with primary TMZ chemotherapy, and analyzed = toxicity,=20 response to therapy and survival parameters in these patients. The best = response=20 to therapy was assessed in the absence of steroids by contrast-enhanced = MRI=20 according to the criteria established by Macdonald et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR7">7</A></CITE>].=20 Toxicity was graded according to the World Health Organization = classification.=20 </P> <P class=3D"">For the analysis of the MGMT promoter methylation status, = genomic=20 DNA was extracted from formalin-fixed paraffin-embedded tumor samples = and=20 subjected to bisulfite conversion using the EZ DNA Methylation-Gold=20 Kit<SUP>=99</SUP> (HISS Diagnostics, Freiburg, Germany) or the EpiTect = Bisulfite=20 Kit (Qiagen, Hilden, Germany). Bisulfite converted DNA was then analyzed = by the=20 authors using methylation-specific PCR (MSP) [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR8">8</A></CITE>]=20 or direct pyrosequencing [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR9">9</A></CITE>]=20 in all patients with a sufficient amount of paraffin-embedded tumor = tissue=20 available (for detailed descriptions of the methylation assays, see = [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR8">8</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR9">9</A></CITE>]).=20 </P></DIV> <DIV class=3D""><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3DPara> <DIV class=3D"">Seventeen patients with histologically proven PCNSL and = a median=20 age of 75 years (range 62=9690 years; Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>)=20 who received first-line therapy with TMZ = (100=96200 mg/m<SUP>2</SUP> on days=20 1=965 of a 28-day cycle) were identified. Two of the 17 patients have = been=20 previously reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR10">10</A></CITE>].=20 HD-MTX therapy was regarded inappropriate because of impaired renal = function=20 (patients 3, 4, 6, 12 of Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>),=20 high age (patients 5, 7, 9, 11, 13=9617), problems with fluid and = electrolyte=20 balance due to a syndrome of inadequate antidiuretic hormone secretion = (SIADH;=20 patient 1), extensive edema (patient 2), severe cardiovascular disease = (patient=20 10), or non-compliance due to oligophrenia (patient 8). The median = number of TMZ=20 cycles applied was three (range 1=968 cycles).<A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Patient=20 characteristics, treatment outcome and MGMT promoter methylation status = of=20 patients with primary central nervous system lymphoma treated with = first-line=20 temozolomide (TMZ) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Patient no.</P></TH> <TH align=3Dleft> <P class=3D"">Age at diagnosis (years), gender</P></TH> <TH align=3Dleft> <P class=3D"">Dose (mg/m<SUP>2</SUP>/d), No. of TMZ = cycles<SUP>a</SUP>=20 </P></TH> <TH align=3Dleft> <P class=3D"">Response to TMZ<SUP>b</SUP> </P></TH> <TH align=3Dleft> <P class=3D"">PFS (months)</P></TH> <TH align=3Dleft> <P class=3D"">Further therapy at relapse (response)</P></TH> <TH align=3Dleft> <P class=3D"">OS (months)</P></TH> <TH align=3Dleft> <P class=3D"">MGMT status</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">63, m</P></TD> <TD align=3Dleft> <P class=3D"">200, 8 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">72+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">72+</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">75, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 4 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">7 =D7 TMZ (PR) and WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">78, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD> <TD align=3Dleft> <P class=3D"">1 =D7 PCV (NA), WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">33</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">4</P></TD> <TD align=3Dleft> <P class=3D"">72, f</P></TD> <TD align=3Dleft> <P class=3D"">150, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">72, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">WBRT (NA)</P></TD> <TD align=3Dleft> <P class=3D"">8</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">6</P></TD> <TD align=3Dleft> <P class=3D"">77, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">7</P></TD> <TD align=3Dleft> <P class=3D"">90, f</P></TD> <TD align=3Dleft> <P class=3D"">100, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">7</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">8</P></TD> <TD align=3Dleft> <P class=3D"">62, m</P></TD> <TD align=3Dleft> <P class=3D"">200, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">5</P></TD> <TD align=3Dleft> <P class=3D"">3 =D7 TMZ (PD), PCV (NA)</P></TD> <TD align=3Dleft> <P class=3D"">9</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">9</P></TD> <TD align=3Dleft> <P class=3D"">88, f</P></TD> <TD align=3Dleft> <P class=3D"">100, 4 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">4</P></TD> <TD align=3Dleft> <P class=3D"">Rituximab (NA)</P></TD> <TD align=3Dleft> <P class=3D"">5+</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">10</P></TD> <TD align=3Dleft> <P class=3D"">73, m</P></TD> <TD align=3Dleft> <P class=3D"">200, 2 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">24+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">24+</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">11</P></TD> <TD align=3Dleft> <P class=3D"">82, f</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">12</P></TD> <TD align=3Dleft> <P class=3D"">67, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 2 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">WBRT (CR)</P></TD> <TD align=3Dleft> <P class=3D"">16+</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">13</P></TD> <TD align=3Dleft> <P class=3D"">81, m</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">−</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">14</P></TD> <TD align=3Dleft> <P class=3D"">75, f</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">1</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">15</P></TD> <TD align=3Dleft> <P class=3D"">74, m</P></TD> <TD align=3Dleft> <P class=3D"">150, 1 cycle</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">26+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">26+</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">16</P></TD> <TD align=3Dleft> <P class=3D"">85, m</P></TD> <TD align=3Dleft> <P class=3D"">150, 3 cycles</P></TD> <TD align=3Dleft> <P class=3D"">PD</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD> <TD align=3Dleft> <P class=3D"">None</P></TD> <TD align=3Dleft> <P class=3D"">3</P></TD> <TD align=3Dleft> <P class=3D"">NA</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">17</P></TD> <TD align=3Dleft> <P class=3D"">80, f</P></TD> <TD align=3Dleft> <P class=3D"">200, 8 cycles</P></TD> <TD align=3Dleft> <P class=3D"">CR</P></TD> <TD align=3Dleft> <P class=3D"">29+</P></TD> <TD align=3Dleft> <P class=3D"">Still in CR</P></TD> <TD align=3Dleft> <P class=3D"">29+</P></TD> <TD align=3Dleft> <P class=3D"">+</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>m</I> male, <I>f</I> female, <I>NA</I> not = assessable,=20 <I>PFS</I> progression-free survival, <I>OS</I> overall survival, = <I>CR</I>=20 complete response, <I>PR</I> partial response, <I>PD</I> progressive = disease,=20 <I>TMZ</I> temozolomide; <I>PCV</I> procarbazine, <I>CCNU</I> = vincristine,=20 <I>WBRT</I> whole brain radiotherapy (39.6=9645 Gy), <I>MGMT</I>=20 O<SUP>6</SUP>-methylguanine-DNA methyltransferase, + methylated MGMT = promoter; −=20 non-methylated MGMT promoter </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>a</SUP>All patients received standard TMZ treatment = (days 1=20 to 5 out of a 28-day cycle) </DIV></DIV> <DIV class=3DCaptCont> <DIV class=3D""><SUP>b</SUP>All patients were off steroids at the time = of response=20 evaluation </DIV></DIV></DIV></DIV></DIV> <P class=3D"">Two patients (12%) developed WHO high-grade hematoxicity: = patient 3=20 had grade 4 leukopenia and thrombocytopenia with subsequent severe = infection;=20 patient 4 had grade 4 leukopenia and grade 3 thrombopenia. One patient = (no. 8)=20 developed grade 1 skin erythema, which might possibly be associated with = TMZ=20 therapy. One patient (no. 15) had to discontinue treatment due to=20 spondylodiscitis, and another patient (no. 5) had grade 2 colitis with = an=20 unclear causal association to TMZ therapy. </P> <DIV class=3DPara> <DIV class=3D"">Eight patients (47%) had a complete response (CR), one = patient had=20 a partial response (PR), and another eight patients had progressive = disease (PD)=20 (Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>).=20 The median progression-free survival (mPFS) was 5 months (range = 1=9672+=20 months; Fig. <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Fig1">1</A>a).=20 Five of 17 patients (29.4%) had prolonged responses for more than=20 12 months. The median overall survival (mOS) was 21 months = (range=20 1=9672+ months; Fig. <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Fig1">1</A>b).=20 The estimated 2-year survival rate was 39.7%. Second- and third-line = therapies=20 are listed in Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>.=20 In four patients (patients 2, 4, 5, and 12), progression-free survival = (PFS)=20 after second-line WBRT was longer than PFS after primary TMZ = chemotherapy.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_32_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/01873364r8l55334/MediaObjects/= 11060_2009_32_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Kaplan=96Meier=20 estimates are shown for <B>a</B> progression-free survival (median,=20 5 months) and <B>b</B> overall survival (median, 21 months) in = 17=20 elderly patients with primary central nervous system lymphoma treated = with=20 first-line TMZ chemotherapy </DIV> <HR> </DIV></DIV> <P class=3D"">Tumor specimens of ten patients were available for MGMT = analysis.=20 MGMT promoter methylation (mMGMT; Table <A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#Tab1">1</A>)=20 in the tumor tissue was found in six patients, while four patients had a = non-methylated MGMT promoter (nmMGMT). Overall survival was 21+ months = in the=20 group of mMGMT patients, whereas mOS was 9 months in the group of = nmMGMT=20 patients. Furthermore, mPFS was 5+ months in mMGMT patients and = 3 months in=20 nmMGMT patients. Of note, three of the five patients surviving for=20 24 months or more had a methylated MGMT promoter, while MGMT was = not=20 assessable in two of these patients. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">First-line chemotherapy with TMZ shows good tolerability = and some=20 activity in elderly PCNSL patients. CR rate (47%), mPFS (5 months) = and mOS=20 (21 months) compare well to presumably more toxic regimens such as=20 chemotherapy on a HD-MTX, lomustine and procarbazine base (CR rate = 42=9647%, mPFS=20 5.9=966.8 months and mOS 14.3=9615.4 months) [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR12">12</A></CITE>].=20 Survival with TMZ monotherapy is somewhat shorter than with a = combination of=20 HD-MTX and TMZ (CR 55%, mPFS 8 months, mOS 35 months) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR13">13</A></CITE>].=20 However, it is possible that selection bias negatively impacted survival = data in=20 our study because many older patients with severe comorbidities = participated in=20 the study. </P> <P class=3D"">Similar to what has been shown for the combination of=20 HD-MTX/lomustine/procarbazine [<CITE><A=20 href=3D"http://www.springerlink.com/content/01873364r8l55334/fulltext.htm= l#CR12">12</A></CITE>],=20 our patient population falls into two subgroups: (1) the larger group of = patients not responding at all to chemotherapy or rapidly progressing = after a=20 very short period of response and (2) the smaller group of patients = deriving=20 notable benefit from chemotherapy with extended PFS and a high potential = for=20 long-term survival (4 of 17 patients surviving relapse-free for = substantially=20 more than 2 years). Our MGMT promoter methylation data are = compatible with=20 the notion that sustained response and prolonged survival are not = possible in=20 the presence of a non-methylated MGMT promoter (PFS 1=963 months). = Since none=20 of the patients surviving more than 24 months had a non-methylated = MGMT=20 promoter, it may be speculated that a methylated MGMT promoter is a = necessary=20 prerequisite for a sustained response. However, a methylated MGMT = promoter=20 cannot be the only molecular factor influencing response and survival = since=20 three of our patients with a methylated MGMT promoter nevertheless had a = short=20 PFS of less than 5 months. Certainly, our limited MGMT data do not=20 sufficiently substantiate this hypothesis, which has to be further = explored in=20 trials that apply alkylating agents to patients with PCNSL. Only larger = trials=20 will then allow statistical comparison of survival parameters between = mMGMT and=20 nmMGMT patients. Of note, salvage WBRT was an effective therapy in four = of five=20 patients. </P> <P class=3D"">The treatment of elderly patients with PCNSL remains a = challenge.=20 According to our preliminary data, TMZ therapy may be an option for some = of=20 these patients. The efficacy of TMZ therapy and a potentially predictive = power=20 of the MGMT promotor status have to be further explored in larger = prospective=20 trials that should also include quality of life assessments. </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Jahnke K, Korfel A, Martus P, Weller M, = Herrlinger U,=20 Schmittel A, Fischer L, Thiel E, German Primary Central Nervous = System=20 Lymphoma Study Group (G-PCNSL-SG) (2005) High-dose methotrexate = toxicity=20 in elderly patients with primary central nervous system lymphoma. = Ann=20 Oncol 16:445=96449<BR><A = href=3D"http://dx.doi.org/10.1093/annonc/mdi075"=20 target=3D_blank><IMG height=3D20 alt=3DCrossRef=20 = src=3D"http://www.springerlink.com/content/01873364r8l55334/crossref_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADC%252BD2M%252FptVGluw%253D%253D&md5=3D9abd3ccd7f16f7ddc53125c5df684= 13f"=20 target=3D_blank><IMG height=3D20 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/01873364r8l55334/chemport_link= .gif"=20 width=3D65 border=3D0></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D15653703"=20 target=3D_blank><IMG height=3D20 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/01873364r8l55334/pubmed_link.g= if"=20 width=3D65 border=3D0></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>2.</TD> <TD><A name=3DCR2></A>Nelson DF, Martz KL, Bonner H, Nelson JS, = Newall J,=20 Kerman HD, Thomson JW, Murray KJ (1992) Non-Hodgkin=92s lymphoma = of the=20 brain: can high dose, large volume radiation therapy improve = survival?=20 Report on a prospective trial by the Radiation Therapy Oncology = Group=20 (RTOG): RTOG 8315. 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