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Subject: Phase III Trial of Chemotherapy Plus Radiotherapy Compared With Radiotherapy Alone for Pure and Mixed Anaplastic Oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402 -- Cairncross et al. 24 (18): 2707 -- Journal of Clinical Oncology
Date: Sat, 17 Jun 2006 18:36:06 +0200
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<META content=3D"Journal of Clinical Oncology" =
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content=3D"Cairncross, Gregory; Berkey, Brian; Shaw, Edward; Jenkins, =
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<META content=3D"Cairncross, Gregory" name=3Ddc.Contributor>
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content=3D"Phase III Trial of Chemotherapy Plus Radiotherapy Compared =
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      <H2>Phase III Trial of Chemotherapy Plus Radiotherapy Compared =
With=20
      Radiotherapy Alone for Pure and Mixed Anaplastic =
Oligodendroglioma:=20
      Intergroup Radiation Therapy Oncology Group Trial 9402 </H2>
      <P><STRONG></NOBR><NOBR>Gregory Cairncross<SUP></SUP></NOBR>, =
<NOBR>Brian=20
      Berkey<SUP></SUP></NOBR>, <NOBR>Edward Shaw<SUP></SUP></NOBR>,=20
      <NOBR>Robert Jenkins<SUP></SUP></NOBR>, <NOBR>Bernd=20
      Scheithauer<SUP></SUP></NOBR>, <NOBR>David =
Brachman<SUP></SUP></NOBR>,=20
      <NOBR>Jan Buckner<SUP></SUP></NOBR>, <NOBR>Karen =
Fink<SUP></SUP></NOBR>,=20
      <NOBR>Luis Souhami<SUP></SUP></NOBR>, <NOBR>Normand=20
      Laperierre<SUP></SUP></NOBR>, <NOBR>Minesh =
Mehta<SUP></SUP></NOBR>,=20
      <NOBR>Walter Curran<SUP></SUP></NOBR> </STRONG>
      <P><FONT size=3D-1>From the University of Calgary, Calgary, =
Alberta; McGill=20
      University, Montreal, Quebec; University of Toronto, Toronto, =
Ontario,=20
      Canada; American College of Radiology; Thomas Jefferson University =
Medical=20
      Center, Philadelphia, PA; Wake Forest University Medical Center,=20
      Winston-Salem, NC; Mayo Clinic, Rochester, MN; Foundation for =
Cancer=20
      Research, Phoenix, AZ; University of Texas Southwestern Medical =
Center,=20
      Dallas, TX; and the University of Wisconsin, Madison, WI </FONT>
      <P><FONT size=3D-1>Address reprint requests to Gregory Cairncross, =
MD,=20
      Foothills Medical Centre, Department of Clinical Neurosciences, =
1403 29th=20
      St NW, Calgary, Alberta, T2N 2T9, Canada; e-mail: <SPAN=20
      id=3Dem0>jgcairnx{at}ucalgary.ca</SPAN>
      <SCRIPT type=3Dtext/javascript><!--=0A=
 var u =3D "jgcairnx", d =3D "ucalgary.ca"; =
document.getElementById("em0").innerHTML =3D '<a href=3D"mailto:' + u + =
'@' + d + '">' + u + '@' + d + '<\/a>'//--></SCRIPT>
      </FONT>
      <P><A name=3DABS><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            ABSTRACT </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><IMG height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>ABSTRACT</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>P=
URPOSE:=20
      Anaplastic oligodendroglioma (AO) and anaplastic =
oligoastrocytoma<SUP>=20
      </SUP>(AOA) are treated with surgery and radiotherapy (RT) at=20
      diagnosis,<SUP> </SUP>but they also respond to procarbazine, =
lomustine,=20
      and vincristine<SUP> </SUP>(PCV), raising the possibility that =
early=20
      chemotherapy will<SUP> </SUP>improve survival. Furthermore, better =

      outcomes in AO have been<SUP> </SUP>associated with 1p and 19q =
allelic=20
      loss.<SUP> </SUP>
      <P>PATIENTS AND METHODS: Patients with AO and AOA were randomly =
assigned=20
      to PCV chemotherapy<SUP> </SUP>followed by RT versus postoperative =
RT=20
      alone. The primary end<SUP> </SUP>point was overall survival. The =
status=20
      of 1p and 19q alleles<SUP> </SUP>was assessed by fluorescence in =
situ=20
      hybridization.<SUP> </SUP>
      <P>RESULTS: Two hundred eighty-nine eligible patients were =
randomly=20
      assigned<SUP> </SUP>to either PCV plus RT (n =3D 147) or RT alone =
(n =3D 142).=20
      At progression,<SUP> </SUP>80% of patients randomly assigned to RT =
had=20
      chemotherapy. With<SUP> </SUP>3-year follow-up on most patients, =
the=20
      median survival times<SUP> </SUP>were similar (4.9 years after PCV =
plus RT=20
      <I>v</I> 4.7 years after<SUP> </SUP>RT alone; hazard ratio [HR] =
=3D 0.90;=20
      95% CI, 0.66 to 1.24; <I>P</I><SUP> </SUP>=3D .26). =
Progression-free=20
      survival time favored PCV plus RT (2.6<SUP> </SUP>years <I>v</I> =
1.7 years=20
      for RT alone; HR =3D 0.69; 95% CI, 0.52 to 0.91;<SUP> =
</SUP><I>P</I> =3D=20
      .004), but 65% of patients experienced grade 3 or 4 toxicity,<SUP> =

      </SUP>and one patient died. Patients with tumors lacking 1p and =
19q<SUP>=20
      </SUP>(46%) compared with tumors not lacking 1p and 19q had =
longer<SUP>=20
      </SUP>median survival times (&gt; 7 <I>v</I> 2.8 years, =
respectively;=20
      <I>P</I> <IMG alt=3D&#8804; src=3D"http://www.jco.org/math/le.gif" =
border=3D0><SUP>=20
      </SUP>.001); longer progression-free survival was most apparent =
in<SUP>=20
      </SUP>this subset.<SUP> </SUP>
      <P>CONCLUSION: For patients with AO and AOA, PCV plus RT does not =
prolong=20
      survival.<SUP> </SUP>Longer progression-free survival after PCV =
plus RT is=20
      associated<SUP> </SUP>with significant toxicity. Tumors lacking 1p =
and 19q=20
      alleles<SUP> </SUP>are less aggressive or more responsive or =
both.<SUP>=20
      </SUP>
      <P><A name=3DSEC1><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            INTRODUCTION </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>INTRODUCTION</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>A=
naplastic=20
      oligodendroglioma (AO) is a histologically distinct<SUP> =
</SUP>high-grade=20
      glioma that, when copopulated by neoplastic astrocytes,<SUP> =
</SUP>evokes=20
      a diagnosis of anaplastic oligoastrocytoma (AOA).<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R1">1</A></SUP>=20
      In<SUP> </SUP>recent years, the histologic criteria for the =
diagnosis of=20
      AO<SUP> </SUP>and AOA have liberalized, and as a result, the rate =
of=20
      diagnosis<SUP> </SUP>of both has increased. Today, up to 25% of =
newly=20
      diagnosed malignant<SUP> </SUP>gliomas are designated AO or =
AOA.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R1">1</A></SUP><SUP>=20
      </SUP>
      <P>Standard treatment for AO and AOA consists of maximum =
surgical<SUP>=20
      </SUP>resection and radiotherapy (RT).<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R2">2</A></SUP>=20
      Although seldom curative,<SUP> </SUP>long survival is relatively =
common=20
      after such treatment. Median<SUP> </SUP>survival time is also =
relatively=20
      long, ranging from 3 to 5 years.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R3">3</A></SUP><SUP>=20
      </SUP>In North America, initial treatment for AO and AOA has =
often<SUP>=20
      </SUP>included chemotherapy with carmustine or procarbazine,=20
      lomustine,<SUP> </SUP>and vincristine (PCV). Chemotherapy at =
diagnosis has=20
      been justified<SUP> </SUP>on the basis of weak evidence of a =
survival=20
      benefit in studies<SUP> </SUP>of adjuvant carmustine for malignant =
glioma=20
      (trials populated<SUP> </SUP>largely by patients with=20
      glioblastoma).<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R4">4</A></SUP>=20
      Early chemotherapy<SUP> </SUP>for oligodendroglioma was reinforced =
by the=20
      discovery that AO<SUP> </SUP>and AOA are often chemotherapy =
sensitive,=20
      responding dramatically<SUP> </SUP>on computed tomography (CT) or =
magnetic=20
      resonance imaging (MRI)<SUP> </SUP>after exposure to PCV.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R5">5</A>,<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R6">6</A></SUP><SUP>=20
      </SUP>
      <P>To test the hypothesis that PCV plus RT is a better =
initial<SUP>=20
      </SUP>treatment than RT alone for AO and AOA, the Radiation =
Therapy<SUP>=20
      </SUP>Oncology Group (RTOG) and four other oncology cooperatives=20
      undertook<SUP> </SUP>a randomized trial, which opened in 1994.=20
      Anticipating that<SUP> </SUP>chromosomal analysis might identify=20
      clinically important subsets<SUP> </SUP>of patients,<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R7">7</A></SUP>=20
      paraffin sections and blood were requested from<SUP> </SUP>all=20
      participants, and during the trial, the potential prognostic<SUP>=20
      </SUP>and predictive value of 1p and 19q allelic loss in AO was=20
      reported.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R8">8</A>,<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R9">9</A></SUP><SUP>=20
      </SUP>
      <P><A name=3DSEC2><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            PATIENTS AND METHODS </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>PATIENTS AND METHODS</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>P=
atients=20
      age <IMG alt=3D&#8805; src=3D"http://www.jco.org/math/ge.gif" =
border=3D0> 18 years=20
      with a newly diagnosed, supratentorial<SUP> </SUP>AO or AOA were =
eligible.=20
      Anaplasia was based on an evaluation<SUP> </SUP>of the following =
five=20
      microscopic features: tumor cellularity,<SUP> </SUP>nuclear =
pleomorphism,=20
      mitotic activity, vascular proliferation,<SUP> </SUP>and necrosis. =
To be=20
      high grade, the tumor had to contain two<SUP> </SUP>anaplastic =
features,=20
      one of which was frequent mitoses or endothelial<SUP> =
</SUP>proliferation.=20
      To be an oligoastrocytoma, a 25% or greater oligodendroglioma<SUP> =

      </SUP>component was required. The diagnosis was confirmed by =
central<SUP>=20
      </SUP>pathology review on all patients before random assignment.=20
      Eligible<SUP> </SUP>patients also had a Karnofsky performance =
score (KPS)=20
      of <IMG alt=3D&#8805; src=3D"http://www.jco.org/math/ge.gif" =
border=3D0> 60<SUP>=20
      </SUP>and adequate hematologic, pulmonary, renal, and hepatic=20
      function<SUP> </SUP>(absolute neutrophil count <IMG alt=3D&#8805;=20
      src=3D"http://www.jco.org/math/ge.gif" border=3D0> 1.5 <FONT=20
      face=3Darial,helvetica>x</FONT> 10<SUP>9</SUP>/L, platelets <IMG =
alt=3D&#8805;=20
      src=3D"http://www.jco.org/math/ge.gif" border=3D0> 150 <FONT=20
      face=3Darial,helvetica>x</FONT> 10<SUP>9</SUP>/L,<SUP> =
</SUP>oxygen=20
      diffusing capacity <IMG alt=3D&#8805; =
src=3D"http://www.jco.org/math/ge.gif"=20
      border=3D0> 60%, serum creatinine <IMG alt=3D&#8804;=20
      src=3D"http://www.jco.org/math/le.gif" border=3D0> 1.5<FONT=20
      face=3Darial,helvetica>x</FONT> the upper<SUP> </SUP>limit of =
normal [ULN],=20
      total bilirubin <IMG alt=3D&#8804; =
src=3D"http://www.jco.org/math/le.gif" border=3D0>=20
      1.5<FONT face=3Darial,helvetica>x</FONT> ULN, and liver<SUP> =
</SUP>function=20
      tests &lt; 2<FONT face=3Darial,helvetica>x</FONT> ULN). Patients =
with other=20
      serious illnesses<SUP> </SUP>or pregnancy were ineligible. All =
study=20
      centers had institutional<SUP> </SUP>review board approval, and =
all=20
      patients consented in writing.<SUP> </SUP>
      <P><STRONG>Study Design and Treatment</STRONG><BR>Patients were =
randomly=20
      assigned at RTOG headquarters within<SUP> </SUP>8 weeks of =
surgical=20
      diagnosis to either PCV followed by focal<SUP> </SUP>RT (the =
experimental=20
      arm) or to RT alone (the control arm).<SUP> </SUP>Patients were =
stratified=20
      by age younger than 50 years versus<SUP> </SUP>50 years or older, =
KPS of=20
      60 to 70 versus <IMG alt=3D&#8805; =
src=3D"http://www.jco.org/math/ge.gif" border=3D0>=20
      80, and tumor grade<SUP> </SUP>of moderately anaplastic (two to =
three=20
      anaplastic features)<SUP> </SUP>versus highly anaplastic (four to =
five=20
      anaplastic features).<SUP> </SUP>Patients were required to begin =
the=20
      assigned treatment within<SUP> </SUP>1 week of random assignment. =
Random=20
      assignment was performed<SUP> </SUP>by randomized permuted block =
within=20
      each stratification cell.<SUP> </SUP>In the experimental arm, up =
to four=20
      cycles of PCV were to be<SUP> </SUP>administered every 6 weeks =
before RT=20
      as follows: lomustine 130<SUP> </SUP>mg/m<SUP>2</SUP> orally on =
day 1;=20
      procarbazine 75 mg/m<SUP>2</SUP> orally daily on<SUP> </SUP>days 8 =
to 21;=20
      and vincristine 1.4 mg/m<SUP>2</SUP> intravenously on days<SUP> =
</SUP>8=20
      and 29. Doses were calculated using actual body weight, =
reduced<SUP>=20
      </SUP>for toxicity, and not escalated. There was no upper limit =
on<SUP>=20
      </SUP>the dose of vincristine. Compliance was assessed by case=20
      reviews.<SUP> </SUP>
      <P>Except for timing, RT was prescribed identically in the=20
      experimental<SUP> </SUP>and control arms. Patients randomly =
assigned to=20
      PCV plus RT<SUP> </SUP>were required to begin RT within 6 weeks of =
the=20
      final dose of<SUP> </SUP>chemotherapy. The total RT dose was 59.4 =
Gy in 33=20
      fractions<SUP> </SUP>(1.8 Gy each), administered 5 days a week =
(Monday=20
      through Friday).<SUP> </SUP>Megavoltage irradiation (<IMG =
alt=3D&#8805;=20
      src=3D"http://www.jco.org/math/ge.gif" border=3D0> 4 MV) was =
required. RT was=20
      planned<SUP> </SUP>using a gadolinium-enhanced MRI obtained within =
2 weeks=20
      of random<SUP> </SUP>assignment and administered in two phases. =
The=20
      initial treatment<SUP> </SUP>field included the T2-weighted =
abnormality=20
      (ie, tumor plus edema)<SUP> </SUP>plus a 2-cm margin (50.4 Gy in =
28=20
      fractions). The boost field<SUP> </SUP>included the =
gadolinium-enhanced=20
      T1-weighted abnormality (ie,<SUP> </SUP>tumor) plus a 1-cm margin =
(9 Gy in=20
      five fractions). After a<SUP> </SUP>complete resection, the =
surgical=20
      cavity and edema with a 2-cm<SUP> </SUP>margin received the =
initial 50.4=20
      Gy, and the cavity with a 1-cm<SUP> </SUP>margin received the =
final 9-Gy=20
      boost. Quality assurance was<SUP> </SUP>determined by case =
reviews.<SUP>=20
      </SUP>
      <P>Corticosteroid medications were permitted for cerebral =
edema,<SUP>=20
      </SUP>antiemetics were permitted for nausea or vomiting, and=20
      anticonvulsants<SUP> </SUP>were permitted for seizures. Deletions =
of=20
      chromosomes 1p and<SUP> </SUP>19q were evaluated by fluorescence =
in situ=20
      hybridization analysis<SUP> </SUP>on tumor tissue sections as =
described=20
      elsewhere.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R10">10</A></SUP>=20
      The primary<SUP> </SUP>end point was overall survival. Secondary =
end=20
      points were progression-free<SUP> </SUP>survival, frequency of =
severe=20
      (<IMG alt=3D&#8805; src=3D"http://www.jco.org/math/ge.gif" =
border=3D0> grade 3)=20
      treatment toxicities,<SUP> </SUP>and quality of life. Survival=20
      measurements were made from the<SUP> </SUP>date of random =
assignment.<SUP>=20
      </SUP>
      <P><STRONG>Surveillance and Follow-Up</STRONG><BR>Baseline =
examination=20
      included a CBC, pulmonary and biochemistry<SUP> </SUP>screening, =
either=20
      MRI or CT scan, and a complete physical and<SUP> </SUP>neurologic=20
      examination, including a Folstein Mini-Mental Status<SUP>=20
      </SUP>Examination. Quality of life was assessed as described by=20
      Mackworth<SUP> </SUP>et al.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R10">10</A></SUP>=20
      During PCV, blood counts were checked weekly, and serum<SUP>=20
      </SUP>chemistries were checked before each cycle. During RT, =
patients<SUP>=20
      </SUP>were assessed weekly. Follow-up MRI or CT scans were =
performed<SUP>=20
      </SUP>before each cycle of PCV and 4 to 6 weeks after RT. =
Thereafter,<SUP>=20
      </SUP>scans were performed every 3 months during post-treatment =
year<SUP>=20
      </SUP>1, every 4 months during year 2, every 6 months during =
years<SUP>=20
      </SUP>3 to 5, and then annually. Follow-up laboratory =
evaluations,<SUP>=20
      </SUP>general and neurologic examinations, recording of=20
      corticosteroid<SUP> </SUP>requirements, and Mini-Mental Status =
Examination=20
      and quality-of-life<SUP> </SUP>assessments were scheduled =
similarly. Tumor=20
      progression was<SUP> </SUP>defined following Macdonald et =
al<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R11">11</A></SUP>=20
      (25% increase in tumor size<SUP> </SUP>by contrast-enhanced =
imaging, new=20
      lesions, or increasing corticosteroids).<SUP> </SUP>At =
progression, PCV=20
      was recommended for patients randomly assigned<SUP> </SUP>to RT, =
but=20
      otherwise, treatment at recurrence was discretionary.<SUP>=20
      </SUP>Second-line therapy was recorded. Toxicity was graded =
using<SUP>=20
      </SUP>the National Cancer Institute Common Toxicity Criteria =
(version<SUP>=20
      </SUP>1). For RT toxicities, the RTOG acute morbidity criteria =
and<SUP>=20
      </SUP>the RTOG/European Organisation for Research and Treatment =
of<SUP>=20
      </SUP>Cancer late morbidity criteria were used.<SUP> </SUP>
      <P><STRONG>Statistical Analysis</STRONG><BR>Overall and =
progression-free=20
      survival were analyzed by the Kaplan-Meier<SUP> </SUP>method with=20
      one-sided log-rank statistics. The study was designed<SUP> =
</SUP>to enroll=20
      146 patients per arm, giving 80% power to detect a<SUP> </SUP>50% =
increase=20
      in median survival time from 3.8 years in the control<SUP> =
</SUP>group to=20
      5.7 years in the experimental group (hazard ratio [HR]<SUP> =
</SUP>for=20
      death =3D 0.67), with a type I error rate of 0.05. Analyses<SUP> =
</SUP>were=20
      performed on a patient-eligible basis. The Cox proportional<SUP>=20
      </SUP>hazards model was fitted to adjust for stratification =
factors<SUP>=20
      </SUP>and other confounding clinical and genetic variables. =
Quality<SUP>=20
      </SUP>of life and neurologic function will be analyzed and =
reported<SUP>=20
      </SUP>separately.<SUP> </SUP>
      <P><A name=3DSEC3><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            RESULTS </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><IMG height=3D9 =
alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>RESULTS</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
STRONG>Patients</STRONG><BR>From=20
      July 1994 to March 2002, 289 eligible patients from 76<SUP>=20
      </SUP>institutions were randomly assigned to PCV plus RT (n =3D =
147)<SUP>=20
      </SUP>or RT alone (n =3D 142); 50% were enrolled at 12 centers. =
Ten<SUP>=20
      </SUP>randomly assigned patients (five in each arm) were =
declared<SUP>=20
      </SUP>ineligible. In the experimental arm, the reasons for=20
      ineligibility<SUP> </SUP>were varied and included the following: =
pregnancy=20
      (n =3D 1), missing<SUP> </SUP>baseline KPS (n =3D 1), failure to =
obtain a=20
      planning MRI (n =3D<SUP> </SUP>1), incorrect diagnosis (n =3D 1), =
and missing=20
      documentation of<SUP> </SUP>central pathology review (n =3D 1). In =
the=20
      control arm, the reasons<SUP> </SUP>for ineligibility pertained to =
the=20
      diagnosis (n =3D 2) or central<SUP> </SUP>review process. =
Sixty-nine percent=20
      of participants were under<SUP> </SUP>age 50 years, 60% were male, =
88% had=20
      debulking surgery, 90%<SUP> </SUP>had a KPS <IMG alt=3D&#8805;=20
      src=3D"http://www.jco.org/math/ge.gif" border=3D0> 80, and 74% had =
an AO or=20
      oligodendroglioma-dominant<SUP> </SUP>AOA. Moreover, the treatment =
groups=20
      were well balanced with<SUP> </SUP>respect to age, sex, KPS, =
imaging=20
      features, extent of resection,<SUP> </SUP>pure versus mixed =
histology,=20
      degree of anaplasia (moderate <I>v</I><SUP> </SUP>high), and=20
      corticosteroid requirements at baseline (<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#T1">Table=20
      1</A>).<SUP> </SUP>Unstained sections were available for =
fluorescence in=20
      situ hybridization<SUP> </SUP>analysis on 206 (71%) of 289 =
eligible=20
      patients; 1p and 19q deletion<SUP> </SUP>status was successfully=20
      ascertained in 201 patients (70%). The<SUP> </SUP>median duration =
of=20
      follow-up was 5.1 years (range, 3 to 93 months).<SUP> </SUP>
      <P><A name=3DT1><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle =
bgColor=3D#ffffff><STRONG>View this=20
                  table:</STRONG><BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/T1">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View table in a =
separate window'; return true"=20
                  onclick=3D"startTarget('T1', 500, 400); =
this.href=3D'/cgi/content-nw/full/24/18/2707/T1'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/T1"=20
                  target=3DT1>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 1.</B> Clinical =
and=20
                  Molecular Characteristics
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Patient=20
      Disposition and Treatment Delivery</STRONG><BR>The median time =
from=20
      diagnosis to the start of treatment was<SUP> </SUP>5 weeks (range, =
1 to 14=20
      weeks) in the experimental arm and 6<SUP> </SUP>weeks (range, 1 to =
12=20
      weeks) in the control arm (<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#T2">Table=20
      2</A>). Chemotherapy<SUP> </SUP>was delivered per protocol in 72% =
of=20
      patients; minor or acceptable<SUP> </SUP>variations occurred in =
17% and 6%=20
      of patients, respectively.<SUP> </SUP>In 4% of patients, PCV was =
either=20
      administered incorrectly or<SUP> </SUP>could not be verified. =
Fifty-four=20
      percent of patients received<SUP> </SUP>four cycles of PCV (wholly =
or=20
      partly), 22% received three, 10%<SUP> </SUP>received two, 12% =
received=20
      one, and 1% did not receive PCV despite<SUP> </SUP>being randomly =
assigned=20
      to PCV plus RT. Forty-eight percent<SUP> </SUP>of patients =
completed all=20
      four cycles of the dose-intensive<SUP> </SUP>PCV formulation used =
in the=20
      study. The reasons for stopping<SUP> </SUP>PCV were progression or =
death,=20
      toxicity, patient refusal, and<SUP> </SUP>physician preference. RT =
was=20
      administered per protocol or acceptably<SUP> </SUP>in 76% of PCV =
patients=20
      and in 82% of controls; unacceptable<SUP> </SUP>variations =
occurred in 6%=20
      and 8% of patients, respectively.<SUP> </SUP>Because of =
progression,=20
      death, or patient preference, RT was<SUP> </SUP>stopped in 10% of =
patients=20
      in the experimental arm and 5% of<SUP> </SUP>patients in the =
control arm.=20
      RT delivery could not be confirmed<SUP> </SUP>in 7% of patients in =
the=20
      experimental arm and 5% of patients<SUP> </SUP>in the control =
arm.<SUP>=20
      </SUP>
      <P><A name=3DT2><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle =
bgColor=3D#ffffff><STRONG>View this=20
                  table:</STRONG><BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/T2">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View table in a =
separate window'; return true"=20
                  onclick=3D"startTarget('T2', 500, 400); =
this.href=3D'/cgi/content-nw/full/24/18/2707/T2'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/T2"=20
                  target=3DT2>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 2.</B> Patient =
Disposition=20
                  and Treatment Intensity
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Survival</STRONG><BR>Thirty-eight=20
      months after the last patient was enrolled, 158<SUP> </SUP>(55%) =
of 289=20
      patients had died (75 of 147 patients in the experimental<SUP> =
</SUP>arm=20
      and 83 of 142 patients in the control arm). The unadjusted<SUP> =
</SUP>HR=20
      for death after PCV plus RT versus RT alone was 0.90 (95%<SUP> =
</SUP>CI,=20
      0.66 to 1.24; log-rank <I>P</I> =3D .26), indicating that =
survival<SUP>=20
      </SUP>was not prolonged by PCV plus RT at diagnosis. The median=20
      survival<SUP> </SUP>time was 4.9 years in the PCV plus RT group =
and 4.7=20
      years in<SUP> </SUP>the RT group (<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#T3">Table=20
      3</A> and <A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#F1">Fig=20
      1</A>). Progression-free survival<SUP> </SUP>time was prolonged by =
PCV=20
      plus RT (HR =3D 0.69; 95% CI, 0.52 to<SUP> </SUP>0.91; log-rank =
<I>P</I> =3D=20
      .004). Median progression-free survival time<SUP> </SUP>was 2.6 =
years with=20
      PCV plus RT compared with 1.7 years with<SUP> </SUP>RT alone (<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#F2">Fig=20
      2</A>).<SUP> </SUP>
      <P><A name=3DT3><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle =
bgColor=3D#ffffff><STRONG>View this=20
                  table:</STRONG><BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/T3">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View table in a =
separate window'; return true"=20
                  onclick=3D"startTarget('T3', 500, 400); =
this.href=3D'/cgi/content-nw/full/24/18/2707/T3'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/T3"=20
                  target=3DT3>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 3.</B> Overall =
and=20
                  Progression-Free Survival by Treatment Group
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><A=20
      name=3DF1><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F1"><IMG=20
                  height=3D160 alt=3D"Figure 1" hspace=3D10=20
                  =
src=3D"http://www.jco.org/content/vol24/issue18/images/small/zlj018063604=
0001.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (14K):<BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F1">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View figure in a =
separate window'; return true"=20
                  onclick=3D"startTarget('F1', 590, 551); =
this.href=3D'/cgi/content-nw/full/24/18/2707/F1'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/F1"=20
                  target=3DF1>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 1.</B> Kaplan-Meier =
estimates=20
                  of overall survival by treatment group. The hazard =
ratio for=20
                  survival of patients treated with procarbazine, =
lomustine, and=20
                  vincristine (PCV) plus radiotherapy (RT) compared with =
RT=20
                  alone was 0.90 (95% CI, 0.66 to 1.24; <I>P</I> =3D =
.26). MST,=20
                  median survival time.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><A=20
      name=3DF2><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F2"><IMG=20
                  height=3D160 alt=3D"Figure 2" hspace=3D10=20
                  =
src=3D"http://www.jco.org/content/vol24/issue18/images/small/zlj018063604=
0002.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (15K):<BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F2">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View figure in a =
separate window'; return true"=20
                  onclick=3D"startTarget('F2', 590, 551); =
this.href=3D'/cgi/content-nw/full/24/18/2707/F2'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/F2"=20
                  target=3DF2>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 2.</B> Kaplan-Meier =
estimates=20
                  of progression-free survival by treatment group. The =
hazard=20
                  ratio for survival of patients treated with =
procarbazine,=20
                  lomustine, and vincristine (PCV) plus radiotherapy =
(RT)=20
                  compared with RT alone was 0.69 (95% CI, 0.52 to 0.91; =

                  <I>P</I> =3D .004). MST, median survival time.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Safety</STRONG><BR>Patients=20
      randomly assigned to the experimental arm experienced<SUP>=20
      </SUP>significant toxicity. Sixty-five percent of patients (94 =
of<SUP>=20
      </SUP>144 patients) had a grade 3 (48 of 144 patients, 33%) or 4 =
(46<SUP>=20
      </SUP>of 144 patients, 32%) toxic reaction on PCV. The most =
frequent<SUP>=20
      </SUP>severe toxicities were hematologic (n =3D 80), neurologic=20
      (cognitive<SUP> </SUP>or mood change and peripheral or autonomic=20
      neuropathy, n =3D 19),<SUP> </SUP>GI (nausea and vomiting, n =3D =
13), hepatic=20
      (n =3D 6), and dermatologic<SUP> </SUP>(n =3D 6). One =
corticosteroid-dependent=20
      patient developed a severe<SUP> </SUP>pulmonary infection while=20
      neutropenic and died. Serious toxicities<SUP> </SUP>were uncommon =
during=20
      RT. Twelve patients (8%) in the PCV plus<SUP> </SUP>RT arm and =
seven=20
      patients (5%) in the RT arm had grade 3 or<SUP> </SUP>4 toxicity =
(<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#T4">Table=20
      4</A>). Late toxicities were uncommon, occurring<SUP> </SUP>in 4% =
and 5%=20
      of patients in the experimental and control groups,<SUP>=20
      </SUP>respectively. No instances of dementia or radionecrosis =
have<SUP>=20
      </SUP>been reported in either group.<SUP> </SUP>
      <P><A name=3DT4><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle =
bgColor=3D#ffffff><STRONG>View this=20
                  table:</STRONG><BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/T4">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View table in a =
separate window'; return true"=20
                  onclick=3D"startTarget('T4', 500, 400); =
this.href=3D'/cgi/content-nw/full/24/18/2707/T4'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/T4"=20
                  target=3DT4>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 4.</B> Grade 3 or =
4=20
                  Toxicities During Treatment
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Treatment=20
      at Progression</STRONG><BR>For patients randomly assigned to RT, =
PCV at=20
      recurrence was<SUP> </SUP>recommended. In May 2005, 177 (61%) of =
289=20
      patients had experienced<SUP> </SUP>progression, including 76 =
(52%) of 147=20
      patients in the experimental<SUP> </SUP>arm and 101 (71%) of 142 =
controls.=20
      Rates of salvage chemotherapy<SUP> </SUP>differed significantly =
between=20
      the groups. At progression, 81<SUP> </SUP>(80%) of 101 patients =
assigned=20
      to RT received salvage chemotherapy<SUP> </SUP>compared with 29 =
(37%) of=20
      76 patients assigned to PCV plus RT.<SUP> </SUP>In the control =
arm, the=20
      cytotoxics used at progression were<SUP> </SUP>PCV (n =3D 21), =
temozolomide=20
      (n =3D 10), both PCV and temozolomide<SUP> </SUP>(n =3D 11), or =
neither PCV=20
      nor temozolomide (n =3D 12) or were unspecified<SUP> </SUP>(n =3D =
27). In the=20
      experimental arm, a variety of cytotoxics was<SUP> </SUP>used, =
often=20
      temozolomide (n =3D 14). Response to salvage chemotherapy<SUP> =
</SUP>was not=20
      recorded. Other therapies at progression included second<SUP>=20
      </SUP>surgery, focused reirradiation, and investigational =
maneuvers.<SUP>=20
      </SUP>Rates of second surgery also differed significantly =
between<SUP>=20
      </SUP>the groups. Sixty-one (60%) of 101 patients in the control=20
      group<SUP> </SUP>had second surgery compared with 30 (39%) of 76 =
patients=20
      assigned<SUP> </SUP>to PCV plus RT. Whether differences in the =
intensity=20
      or effectiveness<SUP> </SUP>of treatment at recurrence had a=20
      disproportionately favorable<SUP> </SUP>influence on the overall =
survival=20
      of patients in the control<SUP> </SUP>group is open to =
speculation.<SUP>=20
      </SUP>
      <P><STRONG>Chromosomal Analysis</STRONG><BR>Loss of 1p was =
detected in 109=20
      (54%) of 202 informative patients,<SUP> </SUP>including 50 (50%) =
of 101=20
      patients in the PCV plus RT group<SUP> </SUP>and 59 (58%) of 101 =
patients=20
      in the RT group (<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#T5">Table=20
      5</A>). Loss<SUP> </SUP>of 19q was found in 126 (61%) of 205 =
informative=20
      patients, including<SUP> </SUP>62 (61%) of 102 patients in the PCV =
plus RT=20
      group and 64 (62%)<SUP> </SUP>of 103 patients in the RT group. =
Combined=20
      loss of 1p and 19q<SUP> </SUP>was detected in 93 (46%) of 201 =
patients,=20
      including 43 (43%)<SUP> </SUP>of 100 patients in the PCV plus RT =
group and=20
      50 (50%) of 101<SUP> </SUP>patients in the RT group. Combined loss =
was=20
      more frequent in<SUP> </SUP>pure tumors (57% for AO <I>v</I> 14% =
for AOA,=20
      <I>P</I> &lt; .001). Patients<SUP> </SUP>whose tumors had combined =
1p and=20
      19q loss also had longer survival<SUP> </SUP>time. The HR for =
death for=20
      1p- and 19q-deleted patients was<SUP> </SUP>significantly reduced =
compared=20
      with all other patients (HR =3D<SUP> </SUP>0.31; 95% CI, 0.20 to =
0.47;=20
      log-rank <I>P</I> &lt; .001; median overall<SUP> </SUP>survival =
time, not=20
      reached <I>v</I> 2.8 years, respectively; <A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#F3">Fig=20
      3</A>).<SUP> </SUP>Similarly, combined loss of 1p and 19q was =
associated=20
      with a<SUP> </SUP>significantly lower risk of tumor progression =
compared=20
      with<SUP> </SUP>no loss (HR =3D 0.44; 95% CI, 0.32 to 0.62; =
log-rank=20
      <I>P</I> &lt; .001;<SUP> </SUP>median progression-free survival =
time, 4.0=20
      <I>v</I> 1.3 years, respectively).<SUP> </SUP>
      <P><A name=3DT5><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle =
bgColor=3D#ffffff><STRONG>View this=20
                  table:</STRONG><BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/T5">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View table in a =
separate window'; return true"=20
                  onclick=3D"startTarget('T5', 500, 400); =
this.href=3D'/cgi/content-nw/full/24/18/2707/T5'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/T5"=20
                  target=3DT5>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 5.</B> Overall =
and=20
                  Progression-Free Survival by Genotype and Treatment
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><A=20
      name=3DF3><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F3"><IMG=20
                  height=3D160 alt=3D"Figure 3" hspace=3D10=20
                  =
src=3D"http://www.jco.org/content/vol24/issue18/images/small/zlj018063604=
0003.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (15K):<BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F3">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View figure in a =
separate window'; return true"=20
                  onclick=3D"startTarget('F3', 590, 551); =
this.href=3D'/cgi/content-nw/full/24/18/2707/F3'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/F3"=20
                  target=3DF3>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 3.</B> Kaplan-Meier =
estimates=20
                  of overall survival by 1p and 19q deletion. The hazard =
ratio=20
                  for survival of patients with 1p and 19q allelic loss =
compared=20
                  with patients with one of neither allele lost was 0.31 =
(95%=20
                  CI, 0.20 to 0.47; <I>P</I> &lt; .001). MST, median =
survival=20
                  time.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR>There=20
      was no effect of treatment on survival analyzed by genotype<SUP> =
</SUP>(<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#F4">Fig=20
      4</A>). For 1p- and 19q-deleted patients, the HR for death<SUP>=20
      </SUP>after PCV plus RT versus RT alone was 0.81 (95% CI, 0.40 =
to<SUP>=20
      </SUP>1.65; log-rank <I>P</I> =3D .28; median survival time, not =
reached=20
      <I>v</I><SUP> </SUP>6.6 years, respectively). Similarly, for =
patients with=20
      tumors<SUP> </SUP>with other genotypes, treatment had no effect on =

      survival (HR<SUP> </SUP>=3D 0.91; 95% CI, 0.58 to 1.42; log-rank =
<I>P</I> =3D=20
      .33; median survival<SUP> </SUP>time, 2.7 years for PCV plus RT =
<I>v</I>=20
      2.8 years for RT only). The<SUP> </SUP>lower risk of progression =
after PCV=20
      plus RT compared with RT<SUP> </SUP>only was statistically =
significant=20
      only for the patients with<SUP> </SUP>both 1p and 19q deletions =
(HR =3D=20
      0.42; 95% CI, 0.24 to 0.75;<SUP> </SUP>log-rank <I>P</I> =3D .001; =
median=20
      progression-free survival time, not<SUP> </SUP>reached <I>v</I> =
2.6 years,=20
      respectively; <A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#F5">Fig=20
      5</A>). For the other patients,<SUP> </SUP>initial treatment had =
no=20
      significant effect on the risk of progression<SUP> </SUP>(HR =3D =
0.78; 95%=20
      CI, 0.51 to 1.18; log-rank <I>P</I> =3D .12; median =
progression-free<SUP>=20
      </SUP>survival time, 1.4 years for PCV plus RT <I>v</I> 1.0 years =
for=20
      RT<SUP> </SUP>only).<SUP> </SUP>
      <P><A name=3DF4><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F4"><IMG=20
                  height=3D162 alt=3D"Figure 4" hspace=3D10=20
                  =
src=3D"http://www.jco.org/content/vol24/issue18/images/small/zlj018063604=
0004.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (20K):<BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F4">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View figure in a =
separate window'; return true"=20
                  onclick=3D"startTarget('F4', 590, 556); =
this.href=3D'/cgi/content-nw/full/24/18/2707/F4'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/F4"=20
                  target=3DF4>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 4.</B> Kaplan-Meier =
estimates=20
                  of overall survival by treatment and genotype. PCV,=20
                  procarbazine, lomustine, and vincristine; RT, =
radiotherapy;=20
                  MST, median survival time.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><A=20
      name=3DF5><!-- null --></A><BR clear=3Dall>
      <CENTER>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"95%">
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD>
            <TABLE cellSpacing=3D2 cellPadding=3D2>
              <TBODY>
              <TR bgColor=3D#e1e1e1>
                <TD vAlign=3Dtop align=3Dmiddle bgColor=3D#ffffff><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F5"><IMG=20
                  height=3D173 alt=3D"Figure 5" hspace=3D10=20
                  =
src=3D"http://www.jco.org/content/vol24/issue18/images/small/zlj018063604=
0005.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (22K):<BR><NOBR><A=20
                  =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707/F5">[in=20
                  this window]</A><BR><A=20
                  onmouseover=3D"window.status=3D'View figure in a =
separate window'; return true"=20
                  onclick=3D"startTarget('F5', 590, 580); =
this.href=3D'/cgi/content-nw/full/24/18/2707/F5'"=20
                  =
href=3D"http://www.jco.org/cgi/content-nw/full/24/18/2707/F5"=20
                  target=3DF5>[in a new window]</A><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 5.</B> Kaplan-Meier =
estimates=20
                  of progression-free survival by treatment and =
genotype. PCV,=20
                  procarbazine, lomustine, and vincristine; RT, =
radiotherapy;=20
                  MST, median survival time.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Cox=20
      Multivariate Regression Analysis</STRONG><BR>The influence of =
genetic and=20
      clinical variables on survival<SUP> </SUP>was analyzed in the Cox=20
      proportional hazards models with assigned<SUP> </SUP>treatment, =
age, KPS,=20
      and number of anaplastic features as fixed<SUP> </SUP>covariates. =
Loss of=20
      1p, loss of 19q, younger age, normal neurologic<SUP> =
</SUP>function,=20
      moderate anaplasia, debulking surgery, and unifocality<SUP> =
</SUP>on=20
      baseline imaging were independently associated with longer<SUP>=20
      </SUP>overall survival time, whereas sex, race, tumor histology, =
and<SUP>=20
      </SUP>corticosteroid use were not. Loss of 1p, PCV therapy, =
younger<SUP>=20
      </SUP>age, moderate anaplasia, and unifocality predicted longer=20
      progression-free<SUP> </SUP>survival time. Loss of 19q was not =
associated=20
      with progression-free<SUP> </SUP>survival in the final Cox =
model.<SUP>=20
      </SUP>
      <P><A name=3DSEC4><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            DISCUSSION </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>DISCUSSION</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>T=
his=20
      study, conceived in the early 1990s, tested the hypothesis<SUP> =
</SUP>that=20
      a dose-intensive PCV formulation administered immediately<SUP>=20
      </SUP>before RT would prolong the survival of patients with =
newly<SUP>=20
      </SUP>diagnosed AO and AOA compared with RT alone, which was =
then<SUP>=20
      </SUP>the standard of care for all types of anaplastic glioma. =
The<SUP>=20
      </SUP>idea that a recognizable subtype of malignant glioma might =
be<SUP>=20
      </SUP>cured by intensive initial therapy was an exciting =
prospect<SUP>=20
      </SUP>in 1994.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R12">12</A>,<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R13">13</A></SUP>=20
      Instead, this study and a similar trial in Europe<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R14">14</A></SUP><SUP>=20
      </SUP>demonstrate that PCV plus RT at diagnosis is not a better=20
      initial<SUP> </SUP>management strategy for AO and AOA compared =
with RT=20
      alone. Because<SUP> </SUP>most patients in the control group =
received PCV=20
      or similar chemotherapy<SUP> </SUP>at progression, one could argue =
that=20
      this study actually tested<SUP> </SUP>the hypothesis that intense =
initial=20
      therapy with PCV and RT<SUP> </SUP>is superior to sequential =
treatment for=20
      AO and AOA; it is not.<SUP> </SUP>
      <P>This result stands in sharp contrast to the findings in =
the<SUP>=20
      </SUP>study by Stupp et al,<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R15">15</A></SUP>=20
      in which the survival of patients with<SUP> </SUP>glioblastoma was =

      prolonged by temozolomide plus RT at diagnosis.<SUP> </SUP>Why =
might early=20
      chemotherapy be effective for glioblastoma,<SUP> </SUP>a=20
      chemotherapy-resistant cancer, but not oligodendroglioma,<SUP> =
</SUP>a=20
      chemotherapy-sensitive cancer? Two possibilities come to =
mind.<SUP>=20
      </SUP>First, compared with glioblastoma, AO and AOA have =
favorable<SUP>=20
      </SUP>natural histories, which is a characteristic that may be a =
more<SUP>=20
      </SUP>important determinant of survival than any combination or=20
      sequence<SUP> </SUP>of noncurative therapies, like PCV and RT. =
Second,=20
      temozolomide,<SUP> </SUP>which also alkylates DNA, is well =
tolerated=20
      compared with PCV.<SUP> </SUP>Temozolomide can be administered =
daily=20
      during RT without significant<SUP> </SUP>myelosuppression,<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R15">15</A></SUP>=20
      whereas toxicity precludes chemoradiotherapy<SUP> </SUP>with PCV. =
The fact=20
      that progression-free survival was prolonged<SUP> </SUP>by adding =
PCV to=20
      RT at diagnosis suggests that early chemotherapy<SUP> </SUP>may =
have the=20
      potential to improve overall survival as well.<SUP> </SUP>Such =
potential=20
      might be realized by a drug like temozolomide,<SUP> </SUP>which is =
less=20
      toxic and can be administered daily with RT. Indeed,<SUP>=20
      </SUP>temozolomide has significant antioligodendroglioma =
activity.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R16">16</A>,<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R17">17</A></SUP><SUP>=20
      </SUP>
      <P>During the trial, retrospective studies drew attention to =
a<SUP>=20
      </SUP>possible association between 1p and 19q allelic loss and=20
      radiographic<SUP> </SUP>response to PCV, durable response to PCV, =
long=20
      progression-free<SUP> </SUP>survival after RT, and long overall =
survival=20
      in patients with<SUP> </SUP>AO.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R8">8</A>,<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R9">9</A>,<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R18">18</A>-<A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R23">23</A></SUP>=20
      In this study, tumor tissue was available for analysis<SUP> =
</SUP>in 71%=20
      of patients. Codeletion of 1p and 19q was detected in<SUP> =
</SUP>46% of=20
      assessable patients. Patients whose tumors harbored a<SUP>=20
      </SUP>codeletion of 1p and 19q lived far longer than all other=20
      patients.<SUP> </SUP>In the Cox multivariate regression analysis, =
1p loss=20
      and 19q<SUP> </SUP>loss were independent predictors of overall =
survival,=20
      suggesting<SUP> </SUP>that tumors with 1p or 19q loss, but =
especially a=20
      codeletion,<SUP> </SUP>have a more favorable natural history, =
response to=20
      treatment,<SUP> </SUP>or both. Indeed, tumors with 1p and 19q =
codeletion=20
      are a clinically<SUP> </SUP>and biologically distinct subgroup of=20
      oligodendrogliomas.<SUP> </SUP>
      <P>A post hoc analysis of the interaction of treatment and =
genotype<SUP>=20
      </SUP>showed that treatment assignment had no effect on =
survival.<SUP>=20
      </SUP>For both the 1p and 19q codeleted patients and the other=20
      patients,<SUP> </SUP>adding PCV to RT at diagnosis did not prolong =
life.=20
      Of note,<SUP> </SUP>the progression-free survival benefit observed =
in=20
      patients randomly<SUP> </SUP>assigned to PCV plus RT was only=20
      statistically significant in<SUP> </SUP>the 1p and 19q subset. =
This=20
      finding provides further evidence<SUP> </SUP>that loss of 1p and =
19q is=20
      both a predictive and prognostic<SUP> </SUP>marker in AO and AOA,=20
      supporting earlier results linking this<SUP> </SUP>codeletion with =

      radiographic response to PCV.<SUP><A=20
      =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#R8">8</A></SUP>=20
      Whether 1p and<SUP> </SUP>19q loss is a relative or absolute =
marker of=20
      chemotherapy sensitivity<SUP> </SUP>is unresolved by these =
data.<SUP>=20
      </SUP>
      <P>This study successfully examined the treatment of an =
uncommon<SUP>=20
      </SUP>brain tumor, demonstrating that multimodality treatment at=20
      diagnosis<SUP> </SUP>is no more effective in prolonging survival =
than a=20
      measured<SUP> </SUP>approach to initial treatment, using RT and=20
      chemotherapy sequentially,<SUP> </SUP>as needed. Although =
progression-free=20
      survival was prolonged<SUP> </SUP>by early intensive treatment, =
PCV plus=20
      RT at diagnosis was accompanied<SUP> </SUP>by substantial=20
      chemotherapy-related toxicity. Finally, this<SUP> </SUP>study =
confirmed=20
      the biologic and clinical importance of allelic<SUP> </SUP>loss of =

      chromosomes 1p and 19q in AOs and AOAs, setting the<SUP> =
</SUP>stage for=20
      future trials designed specifically for patients with<SUP> =
</SUP>1p and=20
      19q codeletion.<SUP> </SUP>
      <P><A name=3DSEC5><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            Appendix </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>Appendix</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
I>The=20
      following cooperative groups, institutions, and investigators<SUP> =

      </SUP>supported the trial</I>: Radiation Therapy Oncology Group:=20
      Akron<SUP> </SUP>City Hospital, Akron, OH (William Demas, MD); =
Albert=20
      Einstein<SUP> </SUP>Medical Center, Philadelphia, PA (Sucha =
Asbell, MD);=20
      Christiana<SUP> </SUP>Care Health System, Newark, DE (Adam Raben, =
MD);=20
      Cleveland Clinic<SUP> </SUP>Foundation, Cleveland, OH (John Suh, =
MD);=20
      Community Clinical<SUP> </SUP>Oncology Programs (CCOPs) in =
Columbus, OH=20
      (Larry Berk, MD),<SUP> </SUP>Greenville, SC (Jeannette Wilcox, =
MD), Kansas=20
      City, MO (William<SUP> </SUP>Stephenson, MD), Metro-MN, St Louis, =
MN (Paul=20
      Sperduto, MD),<SUP> </SUP>Ochsner Clinic, New Orleans, LA (Carl =
Kardinal,=20
      MD), Southeast<SUP> </SUP>Cancer Control Consortium, =
Winston-Salem, NC=20
      (James Atkins,<SUP> </SUP>MD), and Upstate Carolina, Spartanburg, =
SC=20
      (James Bearden, MD);<SUP> </SUP>Southern Nevada Cancer Research=20
      Foundation, Las Vegas, NV (Raul<SUP> </SUP>Meoz-Mendez, MD); Cross =
Cancer=20
      Institute, Edmonton, Alberta,<SUP> </SUP>Canada (Dorcas Fulton, =
MD)=20
      Dana-Farber Cancer Institute, Boston,<SUP> </SUP>MA (William =
Shipley, MD);=20
      Dartmouth Hitchcock Medical Center,<SUP> </SUP>Lebanon, NH (Eugen =
Hug,=20
      MD); Foundation for Cancer Research<SUP> </SUP>and Education, =
Phoenix, AZ=20
      (David Brachman, MD); Fox Chase Cancer<SUP> </SUP>Center, =
Philadelphia, PA=20
      (Andre Konski, MD); Hamilton Regional<SUP> </SUP>Cancer Center, =
Hamilton,=20
      Ontario, Canada (Anthony Whitton, MD);<SUP> </SUP>Hopital =
Notre-Dame du=20
      CHUM, Montreal, Quebec, Canada (Karl Belanger,<SUP> </SUP>MD); =
Johns=20
      Hopkins Medical Center, Baltimore, MD (Ding-Jen Lee,<SUP> =
</SUP>MD);=20
      Louisiana State University Health Science Center, New =
Orleans,<SUP>=20
      </SUP>LA (Jill Gilbert, MD); London Regional Cancer Center, =
London<SUP>=20
      </SUP>Ontario, Canada (Gregory Cairncross, MD); LDS Hospital, =
Salt<SUP>=20
      </SUP>Lake City, UT (William Sause, MD); Mayo Clinic, Rochester, =
MN<SUP>=20
      </SUP>(Jan Buckner, MD); McGill University, Montreal, Quebec, =
Canada<SUP>=20
      </SUP>(Luis Souhami, MD); M.D. Anderson Cancer Center, Houston, =
TX<SUP>=20
      </SUP>(Ritsuko Komaki, MD); Medical College of Wisconsin, =
Milwaukee,<SUP>=20
      </SUP>WI (Elizabeth Gore, MD); New York University Medical =
Center,<SUP>=20
      </SUP>New York, NY (Michael Gruber, MD); Radiological Associates =
of<SUP>=20
      </SUP>Sacramento, Sacramento, CA (Christopher Jones, MD); State=20
      University<SUP> </SUP>of New York Health Science Center, Brooklyn, =
NY=20
      (Marvin Rotman,<SUP> </SUP>MD); Thomas Jefferson University =
Medical=20
      Center, Philadelphia,<SUP> </SUP>PA (Walter Curran, MD); Tom Baker =
Cancer=20
      Centre, Calgary, Alberta,<SUP> </SUP>Canada (Peter Forsyth, MD);=20
      University of Alabama Birmingham<SUP> </SUP>Medical Center, =
Birmingham, AL=20
      (Ruby Meredith, MD, PhD); University<SUP> </SUP>of California =
Davis=20
      Medical Center, Davis, CA (Janice Ryu, MD);<SUP> </SUP>University =
of=20
      California San Francisco, San Francisco, CA (Michael<SUP> =
</SUP>Prados,=20
      MD); University of Kentucky Medical Center, Louisville,<SUP> =
</SUP>KY (Roy=20
      Patchell, MD): University of Pennsylvania Medical Center,<SUP>=20
      </SUP>Philadelphia, PA (Peter Phillips, MD); University of =
Rochester,<SUP>=20
      </SUP>Rochester, NY (Paul Okunieff, MD); Wake Forest University=20
      Medical<SUP> </SUP>Center, Winston-Salem, NC (Edward Shaw); =
Washington=20
      University,<SUP> </SUP>St Louis, MO (Jeff Michalski, MD), and =
Wayne State=20
      University,<SUP> </SUP>Detroit, MI (Lisa Rogers, MD).<SUP> </SUP>
      <P>Southwest Oncology Group: Cleveland Clinic Foundation, =
Cleveland,<SUP>=20
      </SUP>OH (Thomas Budd, MD); CCOPs=97Columbus, Columbus, OH =
(Philip<SUP>=20
      </SUP>Kuebler, MD, PhD) Montana, Billings, MT (Patrick Cobb, =
MD),<SUP>=20
      </SUP>St Louis, St Louis, MO (Bethany Sleckman, MD), Northwest, =
Puget<SUP>=20
      </SUP>Sound, WA (Dustan Osborne, MD), and Wichita, Wichita, KS=20
      (Dennis<SUP> </SUP>Moore, MD); Henry Ford Hospital, Detroit, MI =
(Robert=20
      Chapman,<SUP> </SUP>MD); Loyola University, Chicago, IL (George =
Kovach,=20
      MD); Ohio<SUP> </SUP>State University, Columbus, OH (Paul =
Manuszak, MD);=20
      Providence<SUP> </SUP>Hospital, Southfield, MI (Howard Terebelo, =
MD);=20
      Puget Sound<SUP> </SUP>Oncology Consortium, Puget Sound, WA (Alex =
Spence,=20
      MD); University<SUP> </SUP>of Colorado, Denver, CO (Russell =
Tolley, MD);=20
      University of<SUP> </SUP>Michigan, Ann Arbor, MI (Laurence Baker, =
DO);=20
      University of<SUP> </SUP>New Mexico, Albuquerque, NM (Cheryl =
Willman, MD);=20
      University<SUP> </SUP>of Texas Southwestern, Dallas, TX (Karen =
Fink, MD,=20
      PhD); and<SUP> </SUP>University of Utah, Salt Lake City, UT =
(Thomas Warr,=20
      MD).<SUP> </SUP>
      <P>North Central Cancer Treatment Group: Medcenter One Health=20
      Systems,<SUP> </SUP>Bismarck, ND (Edward Wos, DO); Cedar Rapids =
Oncology=20
      Project<SUP> </SUP>CCOP, Cedar Rapids, IA (Martin Wiesenfeld, MD); =
Iowa=20
      Oncology<SUP> </SUP>Research Association CCOP, Des Moines, IA =
(Roscoe=20
      Morton, MD);<SUP> </SUP>Michigan Cancer Consortium, Ann Arbor, MI =
(Philip=20
      Stella, MD);<SUP> </SUP>Meritcare Hospital CCOP, Fargo, ND =
(Preston Steen,=20
      MD); Geisinger<SUP> </SUP>Clinic and Medical Center CCOP, =
Danville, PA=20
      (Albert Bernath,<SUP> </SUP>MD); Illinois Oncology Research =
Association=20
      CCOP, Peoria, IL<SUP> </SUP>(John Kugler, MD); Toledo Community =
Hospital=20
      Oncology Program<SUP> </SUP>CCOP, Toledo, OH (Paul Schaefer, MD); =
Mayo=20
      Clinic and Mayo Foundation,<SUP> </SUP>Rochester, MN (Steven =
Alberts, MD);=20
      and CentraCare Clinic, St<SUP> </SUP>Cloud, MN (Harold Windschitl, =

      MD).<SUP> </SUP>
      <P>National Cancer Institute of Canada Clinical Trials Group: =
British<SUP>=20
      </SUP>Columbia Cancer Centre, Fraser Valley Centre, Surrey, =
British<SUP>=20
      </SUP>Columbia, Canada (Alexander Agranovich, MD); Toronto =
Sunnybrook<SUP>=20
      </SUP>Regional Cancer Centre, Toronto, Ontario, Canada; and=20
      University<SUP> </SUP>Health Network, Princess Margaret Hospital, =
Toronto,=20
      Ontario,<SUP> </SUP>Canada (Normand Laperierre, MD).<SUP> </SUP>
      <P>Eastern Cooperative Oncology Group: Beth Israel Deaconess=20
      Hospital,<SUP> </SUP>Boston, MA (Michael Atkins, MD); Guthrie =
Clinic for=20
      Education<SUP> </SUP>and Research, Sayre, PA (Goran Broketa, MD); =
Hennepin=20
      County<SUP> </SUP>Medical Center, Minneapolis, MN (Daniel =
Schneider, MD);=20
      St Anthony's<SUP> </SUP>Medical Center, Rockford, IL (Laura =
Cisneros, MD);=20
      University<SUP> </SUP>of Florida Medical Center, Gainesville, FL =
(Robert=20
      Marsh, MD);<SUP> </SUP>and Western Michigan Cancer Center, =
Kalamazoo, MI=20
      (Raymond Lord<SUP> </SUP>III, MD).<SUP> </SUP>
      <P><A name=3DSEC6><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            Authors' Disclosures of Potential Conflicts of Interest=20
        </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            color=3D#464c53>Authors' Disclosures of...</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>T=
he=20
      authors indicated no potential conflicts of interest.<SUP> </SUP>
      <P><A name=3DSEC7><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            Author Contributions </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><IMG height=3D9 =
alt=3D" "=20
            hspace=3D5 src=3D"http://www.jco.org/icons/toc/dot.gif" =
width=3D11=20
            border=3D0><FONT color=3D#464c53>Author =
Contributions</FONT><BR><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/darrow.gif" width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
BR=20
      clear=3Dall>
      <TABLE cellPadding=3D10 border=3D1>
        <TBODY>
        <TR bgColor=3D#e1e1e1>
          <TD><B>Conception and design:</B> Gregory Cairncross, Edward =
Shaw,=20
            Robert<SUP> </SUP>Jenkins, Bernd Scheithauer, Jan Buckner, =
Minesh=20
            Mehta, Walter<SUP> </SUP>Curran
            <P><B>Financial support:</B> Walter Curran
            <P><B>Administrative support:</B><SUP> </SUP>Gregory =
Cairncross,=20
            Edward Shaw, Robert Jenkins, Bernd Scheithauer,<SUP> =
</SUP>Minesh=20
            Mehta, Walter Curran
            <P><B>Provision of study materials or<SUP> =
</SUP>patients:</B>=20
            Gregory Cairncross, Edward Shaw, Robert Jenkins, Bernd<SUP>=20
            </SUP>Scheithauer, David Brachman, Jan Buckner, Karen Fink, =
Luis=20
            Souhami,<SUP> </SUP>Normand Laperierre, Minesh Mehta, Walter =
Curran
            <P><B>Collection<SUP> </SUP>and assembly of data:</B> Brian =
Berkey,=20
            Robert Jenkins, Bernd Scheithauer,<SUP> </SUP>Minesh Mehta, =
Walter=20
            Curran
            <P><B>Data analysis and interpretation:</B><SUP> =
</SUP>Gregory=20
            Cairncross, Brian Berkey, Edward Shaw, Robert Jenkins,<SUP>=20
            </SUP>David Brachman, Jan Buckner, Karen Fink, Luis Souhami, =

            Normand<SUP> </SUP>Laperierre, Minesh Mehta, Walter Curran
            <P><B>Manuscript writing:</B><SUP> </SUP>Gregory Cairncross, =
Brian=20
            Berkey, Edward Shaw, Robert Jenkins,<SUP> </SUP>Bernd =
Scheithauer,=20
            David Brachman, Jan Buckner, Karen Fink,<SUP> </SUP>Luis =
Souhami,=20
            Normand Laperierre, Minesh Mehta, Walter Curran
            <P><B>Final<SUP> </SUP>approval of manuscript:</B> Gregory=20
            Cairncross, Brian Berkey, Edward<SUP> </SUP>Shaw, Robert =
Jenkins,=20
            Bernd Scheithauer, David Brachman, Jan<SUP> </SUP>Buckner, =
Karen=20
            Fink, Luis Souhami, Normand Laperierre, Minesh<SUP> =
</SUP>Mehta,=20
            Walter Curran
            <P></P></TD></TR></TBODY></TABLE>&nbsp;<BR><SUP></SUP>
      <P><SUP></SUP>
      <P><A name=3DACK><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            ACKNOWLEDGMENTS =
</FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>We are indebted=20
      to the patients who agreed to participate in<SUP> </SUP>this study =
and=20
      also to the nurses and managers at participating<SUP> =
</SUP>institutions,=20
      office staff of the participating groups, and<SUP> </SUP>staff in =
the=20
      pathology and molecular genetics laboratories of<SUP> </SUP>the =
Mayo=20
      Clinic whose support was critical to the success of<SUP> =
</SUP>this large=20
      trial.<SUP> </SUP>
      <P><A name=3DFN><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            NOTES </FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><A=20
      name=3D""><!-- null --></A>Supported by National Cancer Institute =
Grants No.=20
      U10 CA21661<SUP> </SUP>and U10 CA32115 to the Radiation Therapy =
Oncology=20
      Group; U10<SUP> </SUP>CA25224 to the North Central Cancer =
Treatment Group;=20
      CA23318,<SUP> </SUP>CA66636, and CA2115 to the Eastern Cooperative =

      Oncology Group;<SUP> </SUP>and U10 CA37422 to Community Clinical =
Oncology=20
      Programs.<SUP> </SUP>
      <P><A name=3D""><!-- null --></A>Authors' disclosures of potential =
conflicts=20
      of interest and<SUP> </SUP>author contributions are found at the =
end of=20
      this article.<SUP> </SUP>
      <P><A name=3DBIBL><!-- null --></A><BR clear=3Dright>
      <TABLE cellSpacing=3D0 cellPadding=3D0 width=3D"100%" =
bgColor=3D#e1e1e1>
        <TBODY>
        <TR>
          <TD vAlign=3Dcenter align=3Dleft width=3D"5%" =
bgColor=3D#ffffff><IMG=20
            height=3D21 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/rarrow.gif" =
width=3D10></TD>
          <TH vAlign=3Dcenter align=3Dleft width=3D"95%"><FONT =
size=3D+2>&nbsp;&nbsp;=20
            REFERENCES </FONT></TH></TR></TBODY></TABLE>
      <TABLE cellPadding=3D5 align=3Dright border=3D1>
        <TBODY>
        <TR>
          <TH align=3Dleft><FONT size=3D-1><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>Appendix<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>Authors' Disclosures of...<BR></A><A=20
            =
href=3D"http://www.jco.org/cgi/content/full/24/18/2707?ijkey=3Db613fe98b7=
aa82c0702119229b331a58db23f8e1#SEC7"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/uarrow.gif" width=3D11=20
            border=3D0>Author Contributions<BR></A><IMG height=3D9 =
alt=3D" " hspace=3D5=20
            src=3D"http://www.jco.org/icons/toc/dot.gif" width=3D11 =
border=3D0><FONT=20
            =
color=3D#464c53>REFERENCES</FONT><BR></FONT></TH></TR></TBODY></TABLE>&nb=
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2000<!-- HIGHWIRE ID=3D"24:18:2707:21" --><A=20
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16(00)00703-3&amp;link_type=3DDOI">[CrossRef]</A><A=20
        =
href=3D"http://www.jco.org/cgi/external_ref?access_num=3D11020580&amp;lin=
k_type=3DMED">[Medline]</A><!-- /HIGHWIRE --><A=20
        name=3DR22><!-- null --></A>
        <LI value=3D22>van den Bent MJ, Looijenga LHJ, Langenberg K, et =
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        Chromosomal anomalies in oligodendroglial tumors are correlated =
to=20
        clinical features. Cancer 97:1276-1284, 2003<!-- HIGHWIRE =
ID=3D"24:18:2707:22" --><A=20
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href=3D"http://www.jco.org/cgi/external_ref?access_num=3D10.1002/cncr.111=
87&amp;link_type=3DDOI">[CrossRef]</A><A=20
        =
href=3D"http://www.jco.org/cgi/external_ref?access_num=3D12599236&amp;lin=
k_type=3DMED">[Medline]</A><!-- /HIGHWIRE --><A=20
        name=3DR23><!-- null --></A>
        <LI value=3D23>Hoang-Xuan K, Capelle L, Kujas M, et al: =
Temozolomide as=20
        initial treatment for adults with low-grade oligodendrogliomas =
and=20
        oligoastrocytomas and correlation with chromosome 1p deletions. =
J Clin=20
        Oncol 22:3133-3138, 2004<!-- HIGHWIRE ID=3D"24:18:2707:23" --><A =

        =
href=3D"http://www.jco.org/cgi/ijlink?linkType=3DABST&amp;journalCode=3Dj=
co&amp;resid=3D22/15/3133"><NOBR>[Abstract/<FONT=20
        color=3D#cc0000>Free</FONT>=20
        Full&nbsp;Text]</NOBR></A><!-- /HIGHWIRE --></LI></OL>Submitted =
September=20
      28, 2005; accepted January 19, 2006.
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------=_NextPart_000_004C_01C6923C.E551E380
Content-Type: text/css;
	charset="iso-8859-1"
Content-Transfer-Encoding: quoted-printable
Content-Location: http://www.jco.org/jco.css

.TopBar {
	BACKGROUND-IMAGE: url(/icons/banner/bg_top.jpg)
}
TD {
	FONT-SIZE: 12px; COLOR: #000000; FONT-FAMILY: Verdana, Arial, =
Helvetica, sans-serif
}
.TopBarTxt {
	FONT-WEIGHT: bold; FONT-SIZE: 11px; FONT-FAMILY: Arial, Helvetica, =
sans-serif
}
.TopBarTxt A:link {
	FONT-SIZE: 12px; COLOR: #c79100; FONT-FAMILY: Verdana, Arial, =
Helvetica, sans-serif; TEXT-DECORATION: none
}
.TopBarTxt A:active {
	FONT-SIZE: 12px; COLOR: #c79100; FONT-FAMILY: Verdana, Arial, =
Helvetica, sans-serif; TEXT-DECORATION: none
}
.TopBarTxt A:visited {
	FONT-SIZE: 12px; COLOR: #c79100; FONT-FAMILY: Verdana, Arial, =
Helvetica, sans-serif; TEXT-DECORATION: none
}
.TopBarTxt A:hover {
	TEXT-DECORATION: underline
}
.TopBarRight {
	PADDING-RIGHT: 20px; PADDING-BOTTOM: 5px
}
.TopNav {
	FONT-WEIGHT: bold; FONT-SIZE: 13px; PADDING-BOTTOM: 2px; WIDTH: 100px; =
COLOR: #ffffff; PADDING-TOP: 2px; FONT-FAMILY: Arial, Helvetica, =
sans-serif
}
.TopNav A:link {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.TopNav A:active {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.TopNav A:visited {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.TopNav A:hover {
	COLOR: #ffffff; TEXT-DECORATION: underline
}
.TopNavH {
	FONT-WEIGHT: bold; FONT-SIZE: 13px; PADDING-BOTTOM: 2px; WIDTH: 100px; =
COLOR: #000000; PADDING-TOP: 2px; FONT-FAMILY: Arial, Helvetica, =
sans-serif; BACKGROUND-COLOR: #ebab00
}
.TopNavH A:link {
	COLOR: #000000; TEXT-DECORATION: none
}
.TopNavH A:active {
	COLOR: #000000; TEXT-DECORATION: none
}
.TopNavH A:visited {
	COLOR: #000000; TEXT-DECORATION: none
}
.TopNavH A:hover {
	COLOR: #000000; TEXT-DECORATION: underline
}
.BotNav {
	FONT-WEIGHT: bold; FONT-SIZE: 12px; PADDING-BOTTOM: 1px; COLOR: =
#ffffff; PADDING-TOP: 1px; FONT-FAMILY: Arial, Helvetica, sans-serif; =
WHITE-SPACE: nowrap; BACKGROUND-COLOR: #54a4d7
}
.BotNav A:link {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.BotNav A:active {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.BotNav A:visited {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.BotNav A:hover {
	COLOR: #ffffff; TEXT-DECORATION: underline
}
.copyrights {
	PADDING-LEFT: 20px; FONT-SIZE: 10px; PADDING-BOTTOM: 10px; COLOR: =
#676767; LINE-HEIGHT: 16px; FONT-FAMILY: Verdana, Arial, Helvetica, =
sans-serif
}
.copyrights A:link {
	COLOR: #308bc5; TEXT-DECORATION: none
}
.copyrights A:active {
	COLOR: #308bc5; TEXT-DECORATION: none
}
.copyrights A:visited {
	COLOR: #308bc5; TEXT-DECORATION: none
}
.copyrights A:hover {
	COLOR: #308bc5; TEXT-DECORATION: underline
}
.HighWire {
	FONT-SIZE: 10px; COLOR: #676767; FONT-FAMILY: Verdana, Arial, =
Helvetica, sans-serif
}
TD.shadow {
	BACKGROUND-IMAGE: url(/icons/banner/bottom_shadow_brand.gif); =
BACKGROUND-REPEAT: repeat-x
}
BODY {
	FONT-SIZE: 12px; MARGIN: 0px; COLOR: #000000; FONT-FAMILY: Verdana, =
Arial, Helvetica, sans-serif; BACKGROUND-COLOR: #ffffff
}
.BodyContent {
	PADDING-RIGHT: 10px; PADDING-LEFT: 26px; PADDING-BOTTOM: 30px; =
PADDING-TOP: 16px
}
.Title {
	FONT-WEIGHT: bold; FONT-SIZE: 16px; COLOR: #ebab00; FONT-FAMILY: Arial, =
Helvetica, sans-serif
}
.TitleAlt1 {
	FONT-WEIGHT: bold; FONT-SIZE: 16px; COLOR: #a70716; FONT-FAMILY: Arial, =
Helvetica, sans-serif
}
.TitleSub {
	FONT-WEIGHT: bold; COLOR: #096bb5
}
.TitleSubAlt1 {
	FONT-WEIGHT: bold; COLOR: #a70716
}
.TitleSubAlt2 {
	FONT-WEIGHT: bold; FONT-SIZE: 13px; COLOR: #000000
}
.CurrIssTopBorder {
	BORDER-RIGHT: #ebab00 1px solid; BORDER-TOP: #ebab00 1px solid; =
BORDER-LEFT: #ebab00 1px solid; BORDER-BOTTOM: #ebab00 0px solid; =
HEIGHT: 26px; BACKGROUND-COLOR: #ffffff
}
.CurrIssBotBorder {
	BORDER-RIGHT: #ebab00 1px solid; BORDER-TOP: #ebab00 0px solid; =
PADDING-LEFT: 10px; FONT-SIZE: 11px; PADDING-BOTTOM: 20px; BORDER-LEFT: =
#ebab00 1px solid; PADDING-TOP: 5px; BORDER-BOTTOM: #ebab00 1px solid; =
BACKGROUND-COLOR: #ffffff
}
.CurrIssBotBorder A:link {
	TEXT-DECORATION: none
}
.CurrIssBotBorder A:active {
	TEXT-DECORATION: none
}
.CurrIssBotBorder A:visited {
	TEXT-DECORATION: none
}
.CurrIssBotBorder A:hover {
	TEXT-DECORATION: underline
}
.CurrIssMidBorder {
	BORDER-RIGHT: #ebab00 1px solid; PADDING-RIGHT: 10px; BORDER-TOP: =
#ebab00 0px solid; PADDING-LEFT: 20px; BORDER-LEFT: #ebab00 0px solid; =
PADDING-TOP: 5px; BORDER-BOTTOM: #ebab00 0px solid; BACKGROUND-COLOR: =
#ffffff
}
.CurrIssContent {
	FONT-SIZE: 11px; PADDING-BOTTOM: 4px; PADDING-TOP: 2px
}
.CurrIssContent A:link {
	TEXT-DECORATION: none
}
.CurrIssContent A:active {
	TEXT-DECORATION: none
}
.CurrIssContent A:visited {
	TEXT-DECORATION: none
}
.CurrIssContent A:hover {
	TEXT-DECORATION: underline
}
.FontSize11 {
	FONT-SIZE: 11px
}
.FontSmall {
	FONT-SIZE: 11px
}
.FontSmall A:link {
	TEXT-DECORATION: none
}
.FontSmall A:active {
	TEXT-DECORATION: none
}
.FontSmall A:visited {
	TEXT-DECORATION: none
}
.FontSmall A:hover {
	TEXT-DECORATION: underline
}
.HomeBodNav {
	FONT-SIZE: 12px
}
.HomeBodNav A:link {
	TEXT-DECORATION: none
}
.HomeBodNav A:active {
	TEXT-DECORATION: none
}
.HomeBodNav A:visited {
	TEXT-DECORATION: none
}
.HomeBodNav A:hover {
	TEXT-DECORATION: underline
}
.TabH {
	FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #4b4a49; PADDING-TOP: 7px
}
.TabH A:link {
	COLOR: #4b4a49; TEXT-DECORATION: none
}
.TabH A:active {
	COLOR: #4b4a49; TEXT-DECORATION: none
}
.TabH A:visited {
	COLOR: #4b4a49; TEXT-DECORATION: none
}
.TabH A:hover {
	COLOR: #4b4a49; TEXT-DECORATION: underline
}
.Tab {
	FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #ffffff; PADDING-TOP: 7px
}
.Tab A:link {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.Tab A:active {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.Tab A:visited {
	COLOR: #ffffff; TEXT-DECORATION: none
}
.Tab A:hover {
	COLOR: #ffffff; TEXT-DECORATION: underline
}
A:link {
	COLOR: #308bc5; TEXT-DECORATION: none
}
A:visited {
	COLOR: #a70716; TEXT-DECORATION: none
}
A:active {
	COLOR: #308bc5; TEXT-DECORATION: none
}
A:hover {
	COLOR: #ff9966; TEXT-DECORATION: underline
}
.TabBody {
	BORDER-RIGHT: #ebab00 1px solid; BORDER-TOP: #ebab00 0px solid; =
BORDER-LEFT: #ebab00 1px solid; BORDER-BOTTOM: #ebab00 1px solid; =
BACKGROUND-COLOR: #ffffff
}
.TabBodyText {
	FONT-WEIGHT: bold; FONT-SIZE: 11px; COLOR: #676769; FONT-FAMILY: Arial, =
Helvetica, sans-serif
}
.SearchResultBox {
	BORDER-RIGHT: #ebab00 1px solid; BORDER-TOP: #ebab00 1px solid; =
BORDER-LEFT: #ebab00 1px solid; BORDER-BOTTOM: #ebab00 1px solid; =
BACKGROUND-COLOR: #ffffff
}
.SearchResultRightCol {
	PADDING-LEFT: 10px; PADDING-TOP: 120px
}
.SearchResultAuthor {
	PADDING-LEFT: 30px
}
.FontSize10 {
	FONT-SIZE: 10px
}
.AtoZ {
	PADDING-BOTTOM: 2px; PADDING-TOP: 8px
}
.AdBoxGrnTxt {
	FONT-SIZE: 11px; COLOR: #318e2f
}
.AdBoxAlt1 {
	BORDER-RIGHT: #e1c2c6 1px solid; PADDING-RIGHT: 3px; BORDER-TOP: =
#e1c2c6 1px solid; PADDING-LEFT: 3px; FONT-SIZE: 10px; PADDING-BOTTOM: =
3px; BORDER-LEFT: #e1c2c6 1px solid; PADDING-TOP: 3px; BORDER-BOTTOM: =
#e1c2c6 1px solid; BACKGROUND-COLOR: #fcf4de
}
.AdBoxAlt2 {
	BORDER-RIGHT: #bababa 1px solid; PADDING-RIGHT: 3px; BORDER-TOP: =
#bababa 1px solid; PADDING-LEFT: 3px; FONT-SIZE: 10px; PADDING-BOTTOM: =
3px; BORDER-LEFT: #bababa 1px solid; PADDING-TOP: 3px; BORDER-BOTTOM: =
#bababa 1px solid; BACKGROUND-COLOR: #fcf4de
}
.BannerHeader {
	PADDING-RIGHT: 55px; PADDING-BOTTOM: 3px; PADDING-TOP: 3px
}
.TableBody {
	BACKGROUND-COLOR: #f9f7f2
}
.TableHead {
	BACKGROUND-COLOR: #bce4ff
}
.FeedbackFAQ {
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Image(),_fa=3D0,_hlfs=3D0,_hoc=3D0,=0A=
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_hck=3D"*; path=3D/; "+(_D("cpd")&&_D("cpd")!=3D""?(" =
domain=3D."+_D("cpd")+"; =
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(_II(navigator.userAgent,'MSIE =
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if(_bnN){if(_bv>3)_ln=3Dnavigator.language;if(_bv>2)for(var =
i=3D0;i<_IL(navigator.plugins);i++)_pl+=3Dnavigator.plugins[i].name+":"};=
_cp=3D_D("cp");=0A=
if(location.search&&_TL(_cp)=3D=3D"null")_cp=3D_J(location.search,"x");if=
(_II(document.cookie,"CP=3D")>-1){=0A=
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"&ja=3D"+(navigator.javaEnabled()?"y":"n")+"&dt=3D"+(new =
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D("hc3"))+"&c4=3D"+=0A=
_A(_D("hc4"))+"&customerid=3D"+_A(_D("ci")?_ci:_D("cid"))+"&lv.id=3D"+_lv=
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if(_I5||_N6){eval("try{_rf=3D_A(top.document"+__r+")+''}"+__c+"{_rf=3D_A(=
document"+__r+")+''}")}=0A=
else{if(top.document&&_IL(parent.frames)>1){_rf=3D_A(eval("document"+__r)=
)+""}else =
if(top.document){_rf=3D_A(eval("top.document"+__r))+""}}if((_rf=3D=3D_hud=
)||=0A=
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_I(_rf,_D("hqsr"),_D("hqsp"),_hrat);_ar+=3D"&ra=3D"+_A(_hra)+"&rf=3D"+_A(=
_IS(_rf,0,500))+=0A=
"&pl=3D"+_A(_pl)+_hbSendEV();if(_D("onlyMedia")!=3D"y")_hbi.src=3D_ar+"&h=
id=3D"+Math.random();_hbq=3D_IS(_ar,0,_II(_ar,"&hec"));_hbE=3D_NA()}_PV()=
;=0A=
function _Q(a){var b=3D"";b=3Dnew =
Image();b.src=3Da+"&hid=3D"+Math.random()}=0A=
function =
_X(a){if(_ec=3D=3D0){_ec=3D1;a=3Ddocument;if(_NN("lt")||_NN("dlf")||_NN("=
elf")){_LP(a.links,1)}if(_NN("fv"))_FA(a)}}=0A=
function =
_EV(a,b,c){if(a.addEventListener){a.addEventListener(b,c,false)}else =
if(a.attachEvent){a.attachEvent("on"+b,c)}}=0A=
function _EVO(e){return document.all?window.event.srcElement:this} =0A=
_EV(window,"load",_X);_EV(window,(_bnI&&_DD(window.onbeforeunload))?"befo=
reunload":"unload",_FU);setTimeout("_X()",3000);
------=_NextPart_000_004C_01C6923C.E551E380
Content-Type: application/octet-stream
Content-Transfer-Encoding: quoted-printable
Content-Location: http://www.jco.org/javascript/ajax/xmlhttprequest.js

/*=0A=
=0A=
Cross-Browser XMLHttpRequest v1.2=0A=
=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=3D=
=3D=3D=3D=3D=3D=3D=3D=3D=0A=
=0A=
Emulate Gecko 'XMLHttpRequest()' functionality in IE and Opera. Opera =
requires=0A=
the Sun Java Runtime Environment <http://www.java.com/>.=0A=
=0A=
by Andrew Gregory=0A=
http://www.scss.com.au/family/andrew/webdesign/xmlhttprequest/=0A=
=0A=
This work is licensed under the Creative Commons Attribution License. To =
view a=0A=
copy of this license, visit =
http://creativecommons.org/licenses/by-sa/2.5/ or=0A=
send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, =
California=0A=
94305, USA.=0A=
=0A=
Attribution: Leave my name and web address in this script intact.=0A=
=0A=
Not Supported in Opera=0A=
----------------------=0A=
* user/password authentication=0A=
* responseXML data member=0A=
=0A=
Not Fully Supported in Opera=0A=
----------------------------=0A=
* async requests=0A=
* abort()=0A=
* getAllResponseHeaders(), getAllResponseHeader(header)=0A=
=0A=
*/=0A=
// IE support=0A=
if (window.ActiveXObject && !window.XMLHttpRequest) {=0A=
  window.XMLHttpRequest =3D function() {=0A=
    var msxmls =3D new Array(=0A=
      'Msxml2.XMLHTTP.5.0',=0A=
      'Msxml2.XMLHTTP.4.0',=0A=
      'Msxml2.XMLHTTP.3.0',=0A=
      'Msxml2.XMLHTTP',=0A=
      'Microsoft.XMLHTTP');=0A=
    for (var i =3D 0; i < msxmls.length; i++) {=0A=
      try {=0A=
        return new ActiveXObject(msxmls[i]);=0A=
      } catch (e) {=0A=
      }=0A=
    }=0A=
    return null;=0A=
  };=0A=
}=0A=
// Gecko support=0A=
/* ;-) */=0A=
// Opera support=0A=
if (window.opera && !window.XMLHttpRequest) {=0A=
  window.XMLHttpRequest =3D function() {=0A=
    this.readyState =3D 0; // =
0=3Duninitialized,1=3Dloading,2=3Dloaded,3=3Dinteractive,4=3Dcomplete=0A=
    this.status =3D 0; // HTTP status codes=0A=
    this.statusText =3D '';=0A=
    this._headers =3D [];=0A=
    this._aborted =3D false;=0A=
    this._async =3D true;=0A=
    this._defaultCharset =3D 'ISO-8859-1';=0A=
    this._getCharset =3D function() {=0A=
      var charset =3D _defaultCharset;=0A=
      var contentType =3D =
this.getResponseHeader('Content-type').toUpperCase();=0A=
      val =3D contentType.indexOf('CHARSET=3D');=0A=
      if (val !=3D -1) {=0A=
        charset =3D contentType.substring(val);=0A=
      }=0A=
      val =3D charset.indexOf(';');=0A=
      if (val !=3D -1) {=0A=
        charset =3D charset.substring(0, val);=0A=
      }=0A=
      val =3D charset.indexOf(',');=0A=
      if (val !=3D -1) {=0A=
        charset =3D charset.substring(0, val);=0A=
      }=0A=
      return charset;=0A=
    };=0A=
    this.abort =3D function() {=0A=
      this._aborted =3D true;=0A=
    };=0A=
    this.getAllResponseHeaders =3D function() {=0A=
      return this.getAllResponseHeader('*');=0A=
    };=0A=
    this.getAllResponseHeader =3D function(header) {=0A=
      var ret =3D '';=0A=
      for (var i =3D 0; i < this._headers.length; i++) {=0A=
        if (header =3D=3D '*' || this._headers[i].h =3D=3D header) {=0A=
          ret +=3D this._headers[i].h + ': ' + this._headers[i].v + '\n';=0A=
        }=0A=
      }=0A=
      return ret;=0A=
    };=0A=
    this.getResponseHeader =3D function(header) {=0A=
      var ret =3D getAllResponseHeader(header);=0A=
      var i =3D ret.indexOf('\n');=0A=
      if (i !=3D -1) {=0A=
        ret =3D ret.substring(0, i);=0A=
      }=0A=
      return ret;=0A=
    };=0A=
    this.setRequestHeader =3D function(header, value) {=0A=
      this._headers[this._headers.length] =3D {h:header, v:value};=0A=
    };=0A=
    this.open =3D function(method, url, async, user, password) {=0A=
      this.method =3D method;=0A=
      this.url =3D url;=0A=
      this._async =3D true;=0A=
      this._aborted =3D false;=0A=
      this._headers =3D [];=0A=
      if (arguments.length >=3D 3) {=0A=
        this._async =3D async;=0A=
      }=0A=
      if (arguments.length > 3) {=0A=
        opera.postError('XMLHttpRequest.open() - user/password not =
supported');=0A=
      }=0A=
      this.readyState =3D 1;=0A=
      if (this.onreadystatechange) {=0A=
        this.onreadystatechange();=0A=
      }=0A=
    };=0A=
    this.send =3D function(data) {=0A=
      if (!navigator.javaEnabled()) {=0A=
        alert("XMLHttpRequest.send() - Java must be installed and =
enabled.");=0A=
        return;=0A=
      }=0A=
      if (this._async) {=0A=
        setTimeout(this._sendasync, 0, this, data);=0A=
        // this is not really asynchronous and won't execute until the =
current=0A=
        // execution context ends=0A=
      } else {=0A=
        this._sendsync(data);=0A=
      }=0A=
    }=0A=
    this._sendasync =3D function(req, data) {=0A=
      if (!req._aborted) {=0A=
        req._sendsync(data);=0A=
      }=0A=
    };=0A=
    this._sendsync =3D function(data) {=0A=
      this.readyState =3D 2;=0A=
      if (this.onreadystatechange) {=0A=
        this.onreadystatechange();=0A=
      }=0A=
      // open connection=0A=
      var url =3D new java.net.URL(new =
java.net.URL(window.location.href), this.url);=0A=
      var conn =3D url.openConnection();=0A=
      for (var i =3D 0; i < this._headers.length; i++) {=0A=
        conn.setRequestProperty(this._headers[i].h, this._headers[i].v);=0A=
      }=0A=
      this._headers =3D [];=0A=
      if (this.method =3D=3D 'POST') {=0A=
        // POST data=0A=
        conn.setDoOutput(true);=0A=
        var wr =3D new =
java.io.OutputStreamWriter(conn.getOutputStream(), this._getCharset());=0A=
        wr.write(data);=0A=
        wr.flush();=0A=
        wr.close();=0A=
      }=0A=
      // read response headers=0A=
      // NOTE: the getHeaderField() methods always return nulls for me :(=0A=
      var gotContentEncoding =3D false;=0A=
      var gotContentLength =3D false;=0A=
      var gotContentType =3D false;=0A=
      var gotDate =3D false;=0A=
      var gotExpiration =3D false;=0A=
      var gotLastModified =3D false;=0A=
      for (var i =3D 0; ; i++) {=0A=
        var hdrName =3D conn.getHeaderFieldKey(i);=0A=
        var hdrValue =3D conn.getHeaderField(i);=0A=
        if (hdrName =3D=3D null && hdrValue =3D=3D null) {=0A=
          break;=0A=
        }=0A=
        if (hdrName !=3D null) {=0A=
          this._headers[this._headers.length] =3D {h:hdrName, =
v:hdrValue};=0A=
          switch (hdrName.toLowerCase()) {=0A=
            case 'content-encoding': gotContentEncoding =3D true; break;=0A=
            case 'content-length'  : gotContentLength   =3D true; break;=0A=
            case 'content-type'    : gotContentType     =3D true; break;=0A=
            case 'date'            : gotDate            =3D true; break;=0A=
            case 'expires'         : gotExpiration      =3D true; break;=0A=
            case 'last-modified'   : gotLastModified    =3D true; break;=0A=
          }=0A=
        }=0A=
      }=0A=
      // try to fill in any missing header information=0A=
      var val;=0A=
      val =3D conn.getContentEncoding();=0A=
      if (val !=3D null && !gotContentEncoding) =
this._headers[this._headers.length] =3D {h:'Content-encoding', v:val};=0A=
      val =3D conn.getContentLength();=0A=
      if (val !=3D -1 && !gotContentLength) =
this._headers[this._headers.length] =3D {h:'Content-length', v:val};=0A=
      val =3D conn.getContentType();=0A=
      if (val !=3D null && !gotContentType) =
this._headers[this._headers.length] =3D {h:'Content-type', v:val};=0A=
      val =3D conn.getDate();=0A=
      if (val !=3D 0 && !gotDate) this._headers[this._headers.length] =
=3D {h:'Date', v:(new Date(val)).toUTCString()};=0A=
      val =3D conn.getExpiration();=0A=
      if (val !=3D 0 && !gotExpiration) =
this._headers[this._headers.length] =3D {h:'Expires', v:(new =
Date(val)).toUTCString()};=0A=
      val =3D conn.getLastModified();=0A=
      if (val !=3D 0 && !gotLastModified) =
this._headers[this._headers.length] =3D {h:'Last-modified', v:(new =
Date(val)).toUTCString()};=0A=
      // read response data=0A=
      var reqdata =3D '';=0A=
      var stream =3D conn.getInputStream();=0A=
      if (stream) {=0A=
        var reader =3D new java.io.BufferedReader(new =
java.io.InputStreamReader(stream, this._getCharset()));=0A=
        var line;=0A=
        while ((line =3D reader.readLine()) !=3D null) {=0A=
          if (this.readyState =3D=3D 2) {=0A=
            this.readyState =3D 3;=0A=
            if (this.onreadystatechange) {=0A=
              this.onreadystatechange();=0A=
            }=0A=
          }=0A=
          reqdata +=3D line + '\n';=0A=
        }=0A=
        reader.close();=0A=
        this.status =3D 200;=0A=
        this.statusText =3D 'OK';=0A=
        this.responseText =3D reqdata;=0A=
        this.readyState =3D 4;=0A=
        if (this.onreadystatechange) {=0A=
          this.onreadystatechange();=0A=
        }=0A=
        if (this.onload) {=0A=
          this.onload();=0A=
        }=0A=
      } else {=0A=
        // error=0A=
        this.status =3D 404;=0A=
        this.statusText =3D 'Not Found';=0A=
        this.responseText =3D '';=0A=
        this.readyState =3D 4;=0A=
        if (this.onreadystatechange) {=0A=
          this.onreadystatechange();=0A=
        }=0A=
        if (this.onerror) {=0A=
          this.onerror();=0A=
        }=0A=
      }=0A=
    };=0A=
  };=0A=
}=0A=
// ActiveXObject emulation=0A=
if (!window.ActiveXObject && window.XMLHttpRequest) {=0A=
  window.ActiveXObject =3D function(type) {=0A=
    switch (type.toLowerCase()) {=0A=
      case 'microsoft.xmlhttp':=0A=
      case 'msxml2.xmlhttp':=0A=
      case 'msxml2.xmlhttp.3.0':=0A=
      case 'msxml2.xmlhttp.4.0':=0A=
      case 'msxml2.xmlhttp.5.0':=0A=
        return new XMLHttpRequest();=0A=
    }=0A=
    return null;=0A=
  };=0A=
}=0A=

------=_NextPart_000_004C_01C6923C.E551E380
Content-Type: application/octet-stream
Content-Transfer-Encoding: quoted-printable
Content-Location: http://www.jco.org/javascript/ajax/utility.js

/************************************************************************=
*****=0A=
 * javascript/ajax/utility.js=0A=
 *=0A=
 * Utility functions for working with XMLHttpRequest data.=0A=
 *=0A=
 * Copyright 2006 Board of Trustees of the Leland Stanford Junior =
University.=0A=
 =
*************************************************************************=
***/=0A=
=0A=
/*=0A=
 * Copy XML nodes into an HTMLElement. This effectively=0A=
 * clones XML markup which uses XHTML naming conventions=0A=
 * into an HTML DOM.=0A=
 */=0A=
function copy_xml_to_html(src, dst) {=0A=
  if (src.nodeType =3D=3D 1) { /* Node.ELEMENT_NODE */=0A=
    var e =3D document.createElement(src.nodeName);=0A=
    for (var i =3D 0; i < src.childNodes.length; i++) {=0A=
	  copy_xml_to_html(src.childNodes[i], e);=0A=
    }=0A=
    for (var i =3D 0; i < src.attributes.length; i++) {=0A=
      var n =3D src.attributes[i].name;=0A=
      var v =3D unescape_xml_string(src.attributes[i].value);      =0A=
      e.setAttribute(n, v);=0A=
      if (n =3D=3D "class") {=0A=
        e.className =3D v;=0A=
      }=0A=
      else if (n =3D=3D "style") {=0A=
        set_css_style(v, e, "");=0A=
      }=0A=
    }=0A=
    dst.appendChild(e);=0A=
  }=0A=
  else if (src.nodeType =3D=3D 3) { /* Node.TEXT_NODE */=0A=
    dst.appendChild(document.createTextNode(src.nodeValue));=0A=
  }=0A=
}=0A=
=0A=
/* =0A=
 * It is unclear that this is the right thing to be calling=0A=
 * from copy_xml_to_html, but it appears that Safari decides=0A=
 * to convert &amp; to the NCR &#35;, and then encodes that=0A=
 * NCR to &%26%2338;.  So, I'm going to treat the DOM Attr=0A=
 * value as a plain string, and run our XML string input=0A=
 * through the decoding routine below.=0A=
 */=0A=
function unescape_xml_string(s) {=0A=
  return s.replace(/&apos;/g, "'")=0A=
          .replace(/&#39;/g,  "'")=0A=
          .replace(/&quot;/g, "\"")=0A=
          .replace(/&#34;/g,  "\"")=0A=
          .replace(/&gt;/g,   ">")=0A=
          .replace(/&#62;/g,  ">")=0A=
          .replace(/&lt;/g,   "<")=0A=
          .replace(/&#60;/g,  "<")=0A=
          .replace(/&amp;/g,  "&")=0A=
          .replace(/&#38;/g,  "&");=0A=
}=0A=
=0A=
/*=0A=
 * Parse set of CSS rules and apply them to an element.=0A=
 * This is quite horrifying, but I'm unable to determine=0A=
 * how else to handle this with IE 6.  FireFox and other=0A=
 * sane browsers let you simply set the style attribute=0A=
 * or use e.style.setProperty(rule, value, priority),=0A=
 * IE 6 appears to have neither of these capabilities..=0A=
 */=0A=
function set_css_style(css, e, priority) {=0A=
  var rules =3D css.split(";");=0A=
  for (var i =3D 0; i < rules.length; i++) {=0A=
    var nvpair =3D rules[i].split(":");=0A=
    if (nvpair.length =3D=3D 2) {=0A=
      try {=0A=
        var name  =3D nvpair[0]; /* style attribute */=0A=
        var value =3D nvpair[1]; /* attribute value */=0A=
  =0A=
        /*=0A=
         * For each possible style attribute, set the=0A=
         * appropriate style property in the element.=0A=
         */=0A=
        if (name =3D=3D "background") {=0A=
           e.style.background =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-attachment") {=0A=
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}=0A=

------=_NextPart_000_004C_01C6923C.E551E380
Content-Type: application/octet-stream
Content-Transfer-Encoding: quoted-printable
Content-Location: http://www.jco.org/javascript/entrez/callback.js

/************************************************************************=
*****=0A=
 * javascript/entrez/callback.js=0A=
 *=0A=
 * Entrez Linking callback to populate content box.=0A=
 *=0A=
 * Copyright 2006 Board of Trustees of the Leland Stanford Junior =
University.=0A=
 =
*************************************************************************=
***/=0A=
=0A=
/*=0A=
 * Execute callback to fill content box with Entrez Linking information.=0A=
 */=0A=
function entrez_callback(pmid, callback_url) {=0A=
  /*=0A=
   * MSIE 5.5 and below have issues with the JavaScript=0A=
   * used for Entrez Linking. For now we have to disable=0A=
   * the callback until we can track down a proper fix=0A=
   * (or everybody sanely upgrades to version 6 or 7!).=0A=
   */=0A=
  if (navigator) {=0A=
    var appname =3D navigator.appName;=0A=
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      }=0A=
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  }=0A=
=0A=
  /*=0A=
   * Acquire table row element to update, initiate callback=0A=
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   */=0A=
  var tr =3D document.getElementById('entrez_callback_'+pmid);=0A=
  if (!tr) {=0A=
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  var req =3D new XMLHttpRequest();=0A=
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  req.open('GET', callback_url, true);=0A=
  req.send(null);=0A=
}=0A=

------=_NextPart_000_004C_01C6923C.E551E380--

