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Subject: Bevacizumab Plus Irinotecan in Recurrent Glioblastoma Multiforme -- Vredenburgh et al. 25 (30): 4722 -- Journal of Clinical Oncology
Date: Mon, 22 Oct 2007 12:02:58 +0200
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      <H2>Bevacizumab Plus Irinotecan in Recurrent Glioblastoma =
Multiforme</H2>
      <P><STRONG></NOBR><NOBR>James J. Vredenburgh<SUP></SUP></NOBR>,=20
      <NOBR>Annick Desjardins<SUP></SUP></NOBR>, <NOBR>James E. Herndon, =

      II<SUP></SUP></NOBR>, <NOBR>Jennifer Marcello<SUP></SUP></NOBR>,=20
      <NOBR>David A. Reardon<SUP></SUP></NOBR>, <NOBR>Jennifer A.=20
      Quinn<SUP></SUP></NOBR>, <NOBR>Jeremy N. Rich<SUP></SUP></NOBR>,=20
      <NOBR>Sith Sathornsumetee<SUP></SUP></NOBR>, <NOBR>Sridharan=20
      Gururangan<SUP></SUP></NOBR>, <NOBR>John =
Sampson<SUP></SUP></NOBR>,=20
      <NOBR>Melissa Wagner<SUP></SUP></NOBR>, <NOBR>Leighann=20
      Bailey<SUP></SUP></NOBR>, <NOBR>Darell D. =
Bigner<SUP></SUP></NOBR>,=20
      <NOBR>Allan H. Friedman<SUP></SUP></NOBR>, <NOBR>Henry S.=20
      Friedman<SUP></SUP></NOBR> </STRONG>
      <P><FONT size=3D-1>From the Preston Robert Tisch Brain Tumor =
Center; and the=20
      Departments of Surgery, Medicine, Biostatistics, Pediatrics, =
Neurobiology,=20
      and Pathology, Duke University Medical Center, Durham, NC </FONT>
      <P><FONT size=3D-1>Address reprint requests to James J. =
Vredenburgh, MD,=20
      Duke University Medical Center, Box 3624, Durham, NC 27710; =
e-mail: <SPAN=20
      id=3Dem0>vrede001{at}mc.duke.edu</SPAN>
      <SCRIPT type=3Dtext/javascript><!--=0A=
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document.getElementById("em0").innerHTML =3D '<a href=3D"mailto:' + u + =
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      <P><A name=3DABS><!-- null --></A><BR clear=3Dright>
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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
            =
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            border=3D0><FONT color=3D#464c53>ABSTRACT</FONT><BR><A=20
            =
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6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
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            border=3D0>INTRODUCTION<BR></A><A=20
            =
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6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
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            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
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6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
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            border=3D0>RESULTS<BR></A><A=20
            =
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6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
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            border=3D0>DISCUSSION<BR></A><A=20
            =
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6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
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            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
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            border=3D0>AUTHORS' DISCLOSURES OF...<BR></A><A=20
            =
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6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
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            =
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6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
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            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>P=
urpose:=20
      The prognosis for patients with recurrent glioblastoma =
multiforme<SUP>=20
      </SUP>is poor, with a median survival of 3 to 6 months. We =
performed<SUP>=20
      </SUP>a phase II trial of bevacizumab, a monoclonal antibody to=20
      vascular<SUP> </SUP>endothelial growth factor, in combination with =

      irinotecan.<SUP> </SUP>
      <P>Patients and Methods: This phase II trial included two cohorts =
of=20
      patients. The initial<SUP> </SUP>cohort, comprising 23 patients, =
received=20
      bevacizumab at 10 mg/kg<SUP> </SUP>plus irinotecan every 2 weeks. =
The dose=20
      of irinotecan was based<SUP> </SUP>on the patient's =
anticonvulsant:=20
      Patients taking enzyme-inducing<SUP> </SUP>antiepileptic drugs =
(EIAEDs)=20
      received 340 mg/m<SUP>2</SUP>, and patients<SUP> </SUP>not taking =
EIAEDs=20
      received 125 mg/m<SUP>2</SUP>. After this regimen was<SUP> =
</SUP>deemed=20
      safe and effective, the irinotecan schedule was changed<SUP> =
</SUP>to an=20
      accepted brain tumor regimen of four doses in 6 weeks,<SUP> =
</SUP>in=20
      anticipation of a phase III randomized trial of irinotecan<SUP>=20
      </SUP>versus irinotecan and bevacizumab. The second cohort,=20
      comprising<SUP> </SUP>12 patients, received bevacizumab 15 mg/kg =
every 21=20
      days and<SUP> </SUP>irinotecan on days 1, 8, 22, and 29. Each =
cycle was 6=20
      weeks<SUP> </SUP>long and concluded with patient evaluations, =
including=20
      magnetic<SUP> </SUP>resonance imaging.<SUP> </SUP>
      <P>Results: The 6-month progression-free survival among all 35=20
      patients<SUP> </SUP>was 46% (95% CI, 32% to 66%). The 6-month =
overall=20
      survival was<SUP> </SUP>77% (95% CI, 64% to 92%). Twenty of the 35 =

      patients (57%; 95%<SUP> </SUP>CI, 39% to 74%) had at least a =
partial=20
      response. One patient<SUP> </SUP>developed a CNS hemorrhage, which =

      occurred in his 10th cycle.<SUP> </SUP>Four patients developed=20
      thromboembolic complications (deep venous<SUP> </SUP>thrombosis =
and/or=20
      pulmonary emboli).<SUP> </SUP>
      <P>Conclusion: Bevacizumab and irinotecan is an effective =
treatment for=20
      recurrent<SUP> </SUP>glioblastoma multiforme and has moderate=20
      toxicity.<SUP> </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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/dot.gif" width=3D11 =

            border=3D0><FONT color=3D#464c53>INTRODUCTION</FONT><BR><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHORS' DISCLOSURES OF...<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHOR CONTRIBUTIONS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>W=
e=20
      performed a phase II trial for patients with recurrent =
glioblastoma<SUP>=20
      </SUP>multiforme (GBM), administering bevacizumab and irinotecan =
in<SUP>=20
      </SUP>combination therapy. A recent phase III randomized trial =
for<SUP>=20
      </SUP>newly diagnosed GBM demonstrated that radiation therapy =
with<SUP>=20
      </SUP>concurrent temozolomide, followed by 6 months of =
temozolomide<SUP>=20
      </SUP>was more efficacious than radiation therapy alone.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R1">1</A></SUP>=20
      However,<SUP> </SUP>the subgroup of patients with methylated =
<I>MGMT</I>=20
      (<I>O</I>6-methylguanine-DNA<SUP> </SUP>methyltransferase) =
promoter=20
      demonstrated benefit from the combination<SUP> </SUP>therapy, as =
opposed=20
      to patients with unmethylated promoter who<SUP> </SUP>did not =
benefit from=20
      the addition of temozolomide.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R2">2</A></SUP>=20
      Irinotecan<SUP> </SUP>is a topoisomerase 1 inhibitor, with a =
different=20
      mechanism of<SUP> </SUP>action than that of alkylating agents such =
as=20
      temozolomide.<SUP> </SUP>Irinotecan has some activity in patients =
with=20
      recurrent GBM,<SUP> </SUP>with response rates of 0% to 17% =
reported for=20
      several trials.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R3">3</A>-<A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R6">6</A></SUP><SUP>=20
      </SUP>The activity of irinotecan is thus similar to that of =
other<SUP>=20
      </SUP>agents used for recurrent GBM.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R7">7</A></SUP><SUP>=20
      </SUP>
      <P>GBM has a high expression of vascular endothelial growth =
factor<SUP>=20
      </SUP>(VEGF),<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R8">8</A></SUP>=20
      a protein that is produced by both tumor cells and<SUP> =
</SUP>stromal=20
      cells, including inflammatory cells.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R9">9</A></SUP>=20
      In human GBM specimens,<SUP> </SUP>the expression of VEGF is =
associated=20
      with a poor prognosis.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R10">10</A></SUP><SUP>=20
      </SUP>Conversely, in a xenograft model, antibodies to VEGF have=20
      inhibited<SUP> </SUP>the growth of GBM.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R11">11</A></SUP><SUP>=20
      </SUP>
      <P>Bevacizumab is a humanized immunoglobulin (Ig) G<SUB>1</SUB>=20
      monoclonal<SUP> </SUP>antibody that binds to and inhibits the =
activity of=20
      VEGF. Bevacizumab<SUP> </SUP>is synergistic with chemotherapy in=20
      colorectal, lung, and breast<SUP> </SUP>carcinomas.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R12">12</A>-<A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R14">14</A></SUP>=20
      As a single agent, bevacizumab prolonged the<SUP> </SUP>time to=20
      progression for patients with metastatic renal cell<SUP> =
</SUP>carcinoma=20
      compared with that for patients receiving placebo.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R15">15</A></SUP><SUP>=20
      </SUP>
      <P>A preliminary report of the combination of bevacizumab and=20
      irinotecan<SUP> </SUP>for patients with malignant gliomas =
demonstrated an=20
      encouraging<SUP> </SUP>response rate of 43%.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R16">16</A></SUP>=20
      There were two treatment-related deaths,<SUP> </SUP>one caused by=20
      intracranial hemorrhage and one by intestinal<SUP> =
</SUP>perforation.=20
      Twenty-three of the patients included in this study<SUP> =
</SUP>were=20
      described in the initial report of the first 32 grade 3<SUP> =
</SUP>or IV=20
      malignant glioma patients.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R17">17</A></SUP>=20
      We report the mature data<SUP> </SUP>for what is to our knowledge =
the=20
      first completed, prospectively<SUP> </SUP>designed phase II trial =
of=20
      bevacizumab and irinotecan for recurrent<SUP> </SUP>GBM.<SUP> =
</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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>INTRODUCTION<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/dot.gif" width=3D11 =

            border=3D0><FONT color=3D#464c53>PATIENTS AND =
METHODS</FONT><BR><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHORS' DISCLOSURES OF...<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHOR CONTRIBUTIONS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
STRONG>Patient=20
      Characteristics</STRONG><BR>Patients were at least 19 years of age =
and had=20
      histologically<SUP> </SUP>proven GBM for which they had received =
radiation=20
      therapy and<SUP> </SUP>temozolomide. All had experienced tumor=20
      progression, had measurable<SUP> </SUP>disease magnetic resonance =
imaging=20
      (MRI), and had recovered<SUP> </SUP>from their prior treatment. A =
minimum=20
      of 6 weeks was required<SUP> </SUP>from prior intracranial =
surgery, and a=20
      minimum of 4 weeks after<SUP> </SUP>radiation and other =
chemotherapeutic=20
      agents, unless there was<SUP> </SUP>evidence of tumor progression. =
The=20
      patients had to have an absolute<SUP> </SUP>neutrophil count more =
than=20
      1,500 =B5L, a hematocrit more<SUP> </SUP>than 29%, and a platelet =
count more=20
      than 125,000 =B5L. The<SUP> </SUP>patients also had to have a =
serum=20
      creatinine less than 1.5 mg/dL,<SUP> </SUP>bilirubin less than 1.5 =
mg/dL,=20
      and serum AST less than 1.5<FONT =
face=3Darial,helvetica>x</FONT><SUP>=20
      </SUP>the upper limit of normal. A patient was excluded if there =
was<SUP>=20
      </SUP>evidence of hemorrhage on the baseline MRI; the patient =
had<SUP>=20
      </SUP>prior malignancy; the patient had previously been treated =
with<SUP>=20
      </SUP>bevacizumab; the patient was a female who was pregnant or=20
      nursing;<SUP> </SUP>or the patient had any other condition that =
would make=20
      the treatment<SUP> </SUP>unsafe. The protocol was reviewed and =
approved by=20
      the US Food<SUP> </SUP>and Drug Administration and the Duke =
University=20
      (Durham, NC)<SUP> </SUP>institutional review board. Each patient =
signed a=20
      written informed<SUP> </SUP>consent and met federal and =
institutional=20
      policies and regulations<SUP> </SUP>as a condition of registering =
for=20
      participation in this study.<SUP> </SUP>
      <P><STRONG>Treatment</STRONG><BR>There were two cohorts of =
recurrent GBM=20
      patients. The first<SUP> </SUP>23 patients received both =
bevacizumab and=20
      irinotecan every 14<SUP> </SUP>days. The bevacizumab was =
administered at=20
      10 mg/kg; the irinotecan<SUP> </SUP>was administered at 340=20
      mg/m<SUP>2</SUP> for patients receiving enzyme-inducing<SUP>=20
      </SUP>antiepileptic drugs (EIAEDs) and 125 mg/m<SUP>2</SUP> for =
patients=20
      not<SUP> </SUP>receiving antiepileptic drugs or receiving =
non-EIAEDs.=20
      After<SUP> </SUP>the first cohort of patients was analyzed, and =
the=20
      regimen was<SUP> </SUP>determined to be active and safe, a second =
group,=20
      including<SUP> </SUP>12 patients, was treated for two reasons: (1) =
to have=20
      an adequate<SUP> </SUP>number of GBM patients to make meaningful=20
      conclusions, and (2)<SUP> </SUP>to change the irinotecan schedule =
to an=20
      accepted GBM treatment<SUP> </SUP>of four doses in 6 weeks in =
anticipation=20
      of a randomized phase<SUP> </SUP>III trial. The second cohort =
received=20
      bevacizumab 15 mg/kg intravenously<SUP> </SUP>every 21 days, and =
the=20
      irinotecan was administered on days 1,<SUP> </SUP>8, 22, and 29 of =
a=20
      42-day cycle. The irinotecan was dosed at<SUP> </SUP>350 =
mg/m<SUP>2</SUP>=20
      for patients receiving EIAEDs and 125 mg/m<SUP>2</SUP> for =
patients<SUP>=20
      </SUP>not receiving antiepileptic drugs or receiving non-EIAEDs. =
For<SUP>=20
      </SUP>those patients on dexamethasone, the dose had to be stable =
for<SUP>=20
      </SUP>at least 7 days before the first cycle, and efforts were =
made<SUP>=20
      </SUP>to maintain the same dose until the tumor assessment was =
done<SUP>=20
      </SUP>after the first cycle.<SUP> </SUP>
      <P>The irinotecan was administered over 90 minutes before the=20
      bevacizumab.<SUP> </SUP>The bevacizumab was administered over 90 =
minutes=20
      for the first<SUP> </SUP>dose, and if the patient had no adverse=20
      reactions, the second<SUP> </SUP>dose was administered over 60 =
minutes and=20
      all subsequent doses<SUP> </SUP>over 30 minutes. The patients had =
to have=20
      hematologic recovery<SUP> </SUP>as documented by an absolute =
neutrophil=20
      count more than 1,000<SUP> </SUP>and platelets more than 100,000 =
before=20
      subsequent infusions.<SUP> </SUP>In addition, the AST enzyme level =
had to=20
      be less than 2.5<FONT face=3Darial,helvetica>x</FONT> normal<SUP> =
</SUP>and=20
      creatinine less than 1.5<FONT face=3Darial,helvetica>x</FONT> =
normal. In the=20
      first cohort of<SUP> </SUP>23 patients, the protein-to-creatinine =
ratio in=20
      a spot urine<SUP> </SUP>specimen had to be less than 1.0 before=20
      re-treatment. In the<SUP> </SUP>second cohort of 12 patients, the =
spot=20
      urine protein-to-creatinine<SUP> </SUP>ratio had to be less than =
3.5=20
      before re-treatment.<SUP> </SUP>
      <P>Patients were allowed a one-time 25% dose reduction of =
irinotecan<SUP>=20
      </SUP>for grade 3 or 4 GI toxicity or a grade 4 hematologic =
toxicity.<SUP>=20
      </SUP>Patients were removed from protocol treatment for any of =
the<SUP>=20
      </SUP>following events: disease progression, patient withdrawal =
of<SUP>=20
      </SUP>consent, development of grade 2 or worse CNS hemorrhage or=20
      grade<SUP> </SUP>4 nonhematologic toxicity, or determination by =
the=20
      investigators<SUP> </SUP>that the treatment regimen was =
unsafe.<SUP>=20
</SUP>
      <P><STRONG>Patient Evaluations</STRONG><BR>Within 14 days of =
initiating=20
      therapy, a full medical history<SUP> </SUP>was taken for all =
patients, and=20
      the patients underwent full<SUP> </SUP>physical and neurologic=20
      examinations, vital sign exam, Karnofsky<SUP> </SUP>status =
determination,=20
      CBC with differential, prothrombin time<SUP> </SUP>and partial=20
      thromboplastin time determinations, serum chemistry<SUP> =
</SUP>profile,=20
      urine test for protein-to-creatinine ratio, and a pregnancy<SUP>=20
      </SUP>test for any woman of child-bearing potential. Within 7 =
days<SUP>=20
      </SUP>of starting treatment, the patient underwent a contrast =
and<SUP>=20
      </SUP>a noncontrast brain MRI, and this MRI examination was =
repeated<SUP>=20
      </SUP>every 6 weeks during treatment. A CBC with differential, =
serum<SUP>=20
      </SUP>chemistry profile, and urine protein-to-creatinine ratio=20
      analysis<SUP> </SUP>were repeated every 2 weeks for the first =
cohort; the=20
      CBC with<SUP> </SUP>differential and serum chemistry profile were =
also=20
      performed<SUP> </SUP>before each irinotecan infusion; and the =
urine=20
      protein-to-creatinine<SUP> </SUP>ratio analysis was performed =
before each=20
      bevacizumab infusion<SUP> </SUP>in the second cohort. A full =
medical=20
      history and physical examination,<SUP> </SUP>including a full =
neurologic=20
      examination, were completed every<SUP> </SUP>6 weeks. The National =
Cancer=20
      Institute Common Terminology Criteria,<SUP> </SUP>version 3.0, was =
used to=20
      evaluate the toxicities.<SUP> </SUP>
      <P><STRONG>Treatment Response Evaluation</STRONG><BR>The response =
to=20
      therapy was determined by two investigators<SUP> </SUP>who =
measured the=20
      tumors independently and agreed on any discrepancies.<SUP> =
</SUP>The=20
      response to therapy was determined by MRI and neurologic<SUP>=20
      </SUP>examination. The investigators utilized the Macdonald =
criteria<SUP>=20
      </SUP>to evaluate the MRI.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R18">18</A></SUP>=20
      The criteria use the largest cross-sectional<SUP> </SUP>area of =
the=20
      postcontrast images and also took into account the<SUP>=20
      </SUP>dexamethasone dose and clinical findings. The =
investigators<SUP>=20
      </SUP>also evaluated the noncontrast T1 images and the T2 and=20
      fluid-attenuated<SUP> </SUP>inversion recovery (FLAIR) images. A =
partial=20
      response was determined<SUP> </SUP>if the contrasted images showed =
a=20
      greater than 50% decrease<SUP> </SUP>in the area of enhancement =
and stable=20
      or decreased T2 and FLAIR<SUP> </SUP>signal, provided that the =
patient was=20
      on a stable or decreased<SUP> </SUP>dose of dexamethasone and also =
was=20
      stable or improved clinically.<SUP> </SUP>A complete response was=20
      determined by the resolution of all<SUP> </SUP>measurable =
abnormalities on=20
      the contrast images, as well as<SUP> </SUP>by stable or decreased =
disease=20
      on T2 and FLAIR images for any<SUP> </SUP>patient who was on a =
stable or=20
      decreased dexamethasone dose<SUP> </SUP>and also was stable and =
improved=20
      clinically. Disease progression<SUP> </SUP>was defined as a =
greater than=20
      25% increase in the area of enhancement,<SUP> </SUP>appearance of =
a new=20
      lesion, or deterioration in the patient's<SUP> </SUP>clinical =
status that=20
      was thought to be related to tumor progression.<SUP> </SUP>The =
patient was=20
      deemed to be stable if the criteria for a partial<SUP> </SUP>or =
complete=20
      response or tumor progression were not met and if<SUP> </SUP>there =
was no=20
      disease progression.<SUP> </SUP>
      <P><STRONG>Statistical Considerations</STRONG><BR>Yung et =
al<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R19">19</A></SUP>=20
      reported that the treatment of GBM patients in<SUP> </SUP>first =
relapse=20
      with temozolomide produced a 6-month progression-free<SUP> =
</SUP>survival=20
      (PFS) rate of 21%, with 95% CI ranging between 13%<SUP> </SUP>and =
29%.=20
      These data were used as the historical basis for the<SUP> =
</SUP>design of=20
      this phase II study. If the true 6-month PFS rate<SUP> </SUP>with=20
      bevacizumab and irinotecan was at least 20%, there would<SUP> =
</SUP>be=20
      interest in further investigation of this combination =
chemotherapy<SUP>=20
      </SUP>treatment. However, if the true 6-month PFS rate was less =
than<SUP>=20
      </SUP>5%, there would be no interest in further studying this=20
      treatment.<SUP> </SUP>With a sample size of 35 patients, the study =
was=20
      designed to<SUP> </SUP>differentiate between 6-month PFS rates of =
5% and=20
      20% with type<SUP> </SUP>I and II error rates of 0.074 and 0.093,=20
      respectively. If five<SUP> </SUP>or more of the 35 patients lived =
at least=20
      6 months without disease<SUP> </SUP>progression, the treatment =
regimen=20
      would be considered worthy<SUP> </SUP>of further study.<SUP> =
</SUP>
      <P>Early stopping rules for unacceptable toxicity were =
defined<SUP>=20
      </SUP>for the occurrence of a grade 2 or worse CNS hemorrhage or=20
      grade<SUP> </SUP>4 or 5 nonhematologic toxicity caused by the =
treatment.=20
      An unacceptable<SUP> </SUP>toxicity rate of 15% or less would not =
be cause=20
      for stopping<SUP> </SUP>the trial, whereas a rate of 40% or =
greater would=20
      signal that<SUP> </SUP>the trial should be stopped. A statistical=20
      hypothesis differentiating<SUP> </SUP>between a 15% and a 40% rate =
of=20
      unacceptable toxicity was tested<SUP> </SUP>with type I and II =
error rates=20
      of 0.053 and 0.053, respectively.<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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.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://jco.ascopubs.org/icons/toc/dot.gif" width=3D11 =

            border=3D0><FONT color=3D#464c53>RESULTS</FONT><BR><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHORS' DISCLOSURES OF...<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHOR CONTRIBUTIONS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
STRONG>Patient=20
      Characteristics</STRONG><BR>Thirty-five patients with =
histologically=20
      documented GBM were<SUP> </SUP>enrolled onto the trial. There were =
22 men=20
      and 13 women, and<SUP> </SUP>the median age was 48 (range, 18 to =
66=20
      years). Every patient<SUP> </SUP>had completed external-beam =
radiation=20
      therapy with concurrent<SUP> </SUP>temozolomide. Three of the =
patients had=20
      experienced disease<SUP> </SUP>progression less than 12 weeks =
after=20
      radiation therapy, and<SUP> </SUP>all three had progression =
outside the=20
      radiation field. If these<SUP> </SUP>three patients are excluded =
from the=20
      analysis, the response<SUP> </SUP>rate, PFS, and overall survival =
reported=20
      below remain unchanged.<SUP> </SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#T1">Table=20
      1</A> lists the relevant patient characteristics. EIAEDs were<SUP> =

      </SUP>used by 15 (43%) of the 35 patients. There were no =
differences<SUP>=20
      </SUP>between the results for the patients who used EIAEDs and =
those<SUP>=20
      </SUP>for the non-EIAEDs patients. Likewise, there were no=20
      statistical<SUP> </SUP>differences between the results for the 23 =
patients=20
      treated<SUP> </SUP>in cohort 1 with every-other-week irinotecan =
plus 10=20
      mg/kg of<SUP> </SUP>bevacizumab and the results for the 12 =
patients=20
      treated in cohort<SUP> </SUP>2 with four doses of irinotecan in a =
6-week=20
      cycle and bevacizumab<SUP> </SUP>at 15 mg/kg every 3 weeks.<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://jco.ascopubs.org/cgi/content/full/25/30/4722/T1">[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('T1', 500, 400); =
this.href=3D'/cgi/content-nw/full/25/30/4722/T1'"=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content-nw/full/25/30/4722/T1"=20
                  target=3DT1>[in a new window]</A><BR><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 1.</B> Patient=20
                  Characteristics
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>PFS</STRONG><BR>The=20
      6-month PFS was 46% (95% CI, 32% to 66%). The median PFS<SUP> =
</SUP>of the=20
      35 GBM patients in the two cohorts was 24 weeks (95%<SUP> =
</SUP>CI, 18 to=20
      36 weeks). There were no statistical differences between<SUP> =
</SUP>the=20
      two cohorts of patients. These PFS data are illustrated<SUP> =
</SUP>by the=20
      Kaplan-Meier curve in <A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#F1">Figure=20
      1</A>.<SUP> </SUP>
      <P><A 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://jco.ascopubs.org/cgi/content/full/25/30/4722/F1"><IMG=20
                  height=3D153 alt=3D"Figure 1" hspace=3D10=20
                  =
src=3D"http://jco.ascopubs.org/content/vol25/issue30/images/small/zlj0300=
765060001.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (8K):<BR><NOBR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/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, 537); =
this.href=3D'/cgi/content-nw/full/25/30/4722/F1'"=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content-nw/full/25/30/4722/F1"=20
                  target=3DF1>[in a new window]</A><BR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/F1">[PowerPoi=
nt=20
                  Slide for Teaching]</A><BR>&nbsp;</NOBR> </TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 1.</B> Kaplan-Meier =

                  progression-free survival (PFS). GBM, glioblastoma =
multiforme.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Overall=20
      Survival</STRONG><BR>The 6-month overall survival was 77% (95% CI, =
64% to=20
      92%). The<SUP> </SUP>median follow-up was 68 weeks (15.5 months). =
The=20
      median overall<SUP> </SUP>survival was 42 weeks (95% CI, 35 to 60 =
weeks).=20
      Overall survival<SUP> </SUP>is presented as a Kaplan-Meier curve =
in <A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#F2">Figure=20
      2</A>.<SUP> </SUP>
      <P><A 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://jco.ascopubs.org/cgi/content/full/25/30/4722/F2"><IMG=20
                  height=3D153 alt=3D"Figure 2" hspace=3D10=20
                  =
src=3D"http://jco.ascopubs.org/content/vol25/issue30/images/small/zlj0300=
765060002.gif"=20
                  width=3D200 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (7K):<BR><NOBR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/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, 537); =
this.href=3D'/cgi/content-nw/full/25/30/4722/F2'"=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content-nw/full/25/30/4722/F2"=20
                  target=3DF2>[in a new window]</A><BR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/F2">[PowerPoi=
nt=20
                  Slide for Teaching]</A><BR>&nbsp;</NOBR> </TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 2.</B> Kaplan-Meier =
overall=20
                  survival (OS). GBM, glioblastoma multiforme.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Response</STRONG><BR>Twenty=20
      of the 35 patients (57%; 95% CI, 39% to 74%) had at least<SUP> =
</SUP>a=20
      partial response to the bevacizumab and irinotecan. Seven<SUP> =
</SUP>of=20
      the patients have completed a full year of therapy, and six<SUP> =
</SUP>of=20
      the seven had a hypometabolic 18-fluorodeoxyglucose (FDG)<SUP> =
</SUP>PET=20
      scan, or "cold" PET, suggesting no residual high-grade tumor<SUP>=20
      </SUP>after the year of therapy. <A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#F3">Figures=20
      3</A> and <A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#F4">4</A>=20
      are examples of the<SUP> </SUP>dramatic responses seen on this =
trial.<SUP>=20
      </SUP>
      <P><A 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://jco.ascopubs.org/cgi/content/full/25/30/4722/F3"><IMG=20
                  height=3D200 alt=3D"Figure 3" hspace=3D10=20
                  =
src=3D"http://jco.ascopubs.org/content/vol25/issue30/images/small/zlj0300=
765060003.gif"=20
                  width=3D166 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (64K):<BR><NOBR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/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', 515, 640); =
this.href=3D'/cgi/content-nw/full/25/30/4722/F3'"=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content-nw/full/25/30/4722/F3"=20
                  target=3DF3>[in a new window]</A><BR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/F3">[PowerPoi=
nt=20
                  Slide for Teaching]</A><BR>&nbsp;</NOBR> </TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 3.</B> Baseline and =

                  post-treatment magnetic resonance imaging of patients =
treated=20
                  with bevacizumab and irinotecan. Postcontrast axial =
and=20
                  coronal T1-weighted magnetic resonance scans in a =
patient with=20
                  glioblastoma multiforme at (A, B) baseline and (C, D) =
after=20
                  four cycles of bevacizumab/irinotecan.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><A=20
      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://jco.ascopubs.org/cgi/content/full/25/30/4722/F4"><IMG=20
                  height=3D200 alt=3D"Figure 4" hspace=3D10=20
                  =
src=3D"http://jco.ascopubs.org/content/vol25/issue30/images/small/zlj0300=
765060004.gif"=20
                  width=3D166 vspace=3D5 border=3D2></A><BR><STRONG>View =
larger=20
                  version</STRONG> (69K):<BR><NOBR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/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', 515, 640); =
this.href=3D'/cgi/content-nw/full/25/30/4722/F4'"=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content-nw/full/25/30/4722/F4"=20
                  target=3DF4>[in a new window]</A><BR><A=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722/F4">[PowerPoi=
nt=20
                  Slide for Teaching]</A><BR>&nbsp;</NOBR> </TD>
                <TD vAlign=3Dtop align=3Dleft><B>Fig 4.</B> Baseline and =

                  post-treatment magnetic resonance imaging of a second =
patient=20
                  treated with bevacizumab and irinotecan. Postcontrast =
axial=20
                  and coronal T1-weighted magnetic resonance scans in a =
patient=20
                  with a glioblastoma multiforme at (A, B) baseline and =
(C, D)=20
                  after four cycles of bevacizumab/and irinotecan.
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><STRONG>Toxicity</STRONG><BR>Eleven=20
      of the 35 patients had to stop receiving therapy secondary<SUP> =
</SUP>to=20
      toxicity. The reasons for which the patients discontinued<SUP>=20
      </SUP>therapy are listed in <A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#T2">Table=20
      2</A>. Of the 11 patients, eight were<SUP> </SUP>in cohort 1 and =
three=20
      were in cohort 2. Two of the patients<SUP> </SUP>in cohort 1 had =
grade 2=20
      proteinuria, which required that the<SUP> </SUP>patients =
discontinue the=20
      study, but the protocol was amended<SUP> </SUP>for cohort 2 to =
allow up to=20
      grade 3 proteinuria before the patient<SUP> </SUP>had to come off =
study.=20
      There may be an increased risk of venous<SUP> </SUP>thromboembolic =
disease=20
      with this therapy; four patients had<SUP> </SUP>to stop therapy =
because of=20
      thromboembolic complications (deep<SUP> </SUP>venous thromboses =
and/or=20
      pulmonary emboli). In addition, three<SUP> </SUP>patients in =
cohort 2 and=20
      one patient in cohort 1 elected to<SUP> </SUP>stop the treatment, =
and all=20
      four cited fatigue as the reason.<SUP> </SUP>There were no =
patients in=20
      cohort 1 who required a dose reduction<SUP> </SUP>for GI toxicity, =
but=20
      four of the 12 in cohort 2 required a dose<SUP> </SUP>reduction =
for grade=20
      3 or worse GI toxicity.<SUP> </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://jco.ascopubs.org/cgi/content/full/25/30/4722/T2">[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('T2', 500, 400); =
this.href=3D'/cgi/content-nw/full/25/30/4722/T2'"=20
                  =
href=3D"http://jco.ascopubs.org/cgi/content-nw/full/25/30/4722/T2"=20
                  target=3DT2>[in a new window]</A><BR><BR>&nbsp;</NOBR> =
</TD>
                <TD vAlign=3Dtop align=3Dleft><B>Table 2.</B> Reasons =
for Patient=20
                  Discontinuation From the Study and Duration of =
Patients on=20
                  Study
                  =
<P></P></TD></TR></TBODY></TABLE></TD></TR></TBODY></TABLE></CENTER>&nbsp=
;<BR><A=20
      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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>RESULTS<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/dot.gif" width=3D11 =

            border=3D0><FONT color=3D#464c53>DISCUSSION</FONT><BR><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHORS' DISCLOSURES OF...<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHOR CONTRIBUTIONS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR>W=
e=20
      report what is to our knowledge the first phase II trial<SUP> =
</SUP>of=20
      irinotecan and bevacizumab for the treatment of recurrent<SUP>=20
      </SUP>GBM.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R17">17</A></SUP>=20
      The study produced some notable results, including a<SUP> =
</SUP>striking=20
      improvement in the 6-month PFS compared with that of<SUP> =
</SUP>historical=20
      controls, as well as a high response rate. Importantly,<SUP> =
</SUP>there=20
      were no early CNS hemorrhages, but there was a suggestion<SUP> =
</SUP>of an=20
      increased risk of thromboembolic complications. Given<SUP> =
</SUP>the=20
      similar efficacy and increased toxicity with the schedules<SUP> =
</SUP>for=20
      cohorts 1 and 2, the schedule for cohort 1, with irinotecan<SUP> =
</SUP>and=20
      bevacizumab administered every other week, will be utilized<SUP> =
</SUP>in=20
      subsequent studies.<SUP> </SUP>
      <P>This study was conducted to improve the prognosis for =
recurrent<SUP>=20
      </SUP>GBM, for which response to therapy has generally been less =
than<SUP>=20
      </SUP>20% and 6-month PFS less than 30%.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R19">19</A>-<A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R22">22</A></SUP>=20
      Although temozolomide<SUP> </SUP>in combination with radiation =
therapy=20
      followed by 6 months of<SUP> </SUP>temozolomide has become the =
standard of=20
      care for newly diagnosed<SUP> </SUP>GBM,<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R1">1</A></SUP>=20
      temozolomide has shown only minimal activity for recurrent<SUP> =
</SUP>GBM=20
      in patients who have received no chemotherapy or a =
nitrosourea-based<SUP>=20
      </SUP>regimen. In the trial reported by Yung et al, <SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R19">19</A></SUP>=20
      the response<SUP> </SUP>rate was 8% and the 6-month PFS 21%. In =
addition,=20
      the 6-month<SUP> </SUP>overall survival with bevacizumab and =
irinotecan=20
      was improved<SUP> </SUP>compared with temozolomide: 77% versus 60% =

      respectively. Our<SUP> </SUP>trial of bevacizumab and irinotecan =
also=20
      compares favorably<SUP> </SUP>with the results detailed by Wong et =
al,=20
      <SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R7">7</A></SUP>=20
      which represents<SUP> </SUP>patients with recurrent GBM, who were =
treated=20
      on one of eight<SUP> </SUP>different chemotherapy trials. =
Comparison of=20
      the current results<SUP> </SUP>show a 6-month PFS and median PFS =
in=20
      patients with GBM of 43%<SUP> </SUP>and 24 weeks, compared with =
the Wong=20
      et al results of 15% and<SUP> </SUP>9 weeks, respectively, in =
patients=20
      with GBM. The 1-year overall<SUP> </SUP>survival is improved in =
our trial=20
      of bevacizumab and irinotecan<SUP> </SUP>compared with the Wong et =
al=20
      results: 37% versus 21%, respectively.<SUP> </SUP>Temozolomide in=20
      combination with other agents such as irinotecan,<SUP> =
</SUP>etoposide, or=20
      erlotinib has produced modest improvements in<SUP> </SUP>the =
response=20
      rates and survival compared with historical controls<SUP> </SUP>of =

      temozolomide alone,<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R23">23</A>-<A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R25">25</A></SUP>=20
      but not as dramatic as bevacizumab<SUP> </SUP>and irinotecan.<SUP> =
</SUP>
      <P>Because the majority of patients fail to respond to =
temozolomide<SUP>=20
      </SUP>in the up-front or recurrent disease setting, clearly, new=20
      regimens<SUP> </SUP>are needed for the more formidable recurrent =
GBM. One=20
      approach<SUP> </SUP>has been to administer nitrosoureas, which are =
also=20
      alkylating<SUP> </SUP>agents, and for which the mechanisms of =
resistance=20
      are similar<SUP> </SUP>to those encountered with temozolomide =
therapy,=20
      particularly,<SUP> </SUP>the resistance enzyme MGMT. As with =
single-agent=20
      temozolomide,<SUP> </SUP>nitrosoureas alone produce response rates =
of less=20
      than 10%,<SUP> </SUP>6-month PFS rates of less than 20%, and =
median=20
      survivals of<SUP> </SUP>6 to 12 weeks.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R26">26</A></SUP>=20
      However, nitrosoureas in combination with procarbazine<SUP> =
</SUP>and=20
      vincristine have resulted in small improvements in response<SUP>=20
      </SUP>rates and survival.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R21">21</A></SUP>=20
      Nitrosoureas in combination with irinotecan<SUP> </SUP>have also =
produced=20
      similar, small increments in response rates<SUP> </SUP>and=20
      survival.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R27">27</A></SUP><SUP>=20
      </SUP>
      <P>Topoisomerase 1 inhibitors, such as irinotecan and =
topotecan,<SUP>=20
      </SUP>have a different mechanism of cytotoxicity from that of=20
      alkylating<SUP> </SUP>agents. In addition, topoisomerase 1 =
inhibitors are=20
      not affected<SUP> </SUP>by the resistance enzyme MGMT. Therefore,=20
      topoisomerase 1 inhibitors<SUP> </SUP>are reasonable therapeutic =
options=20
      for recurrent GBM after failure<SUP> </SUP>of alkylating agents.=20
      Topoisomerase 1 inhibitors have excellent<SUP> </SUP>penetration =
through=20
      the blood-brain barrier, but the treatment<SUP> </SUP>results for=20
      glioblastomas have been disappointing. For example,<SUP> </SUP>the =
rates=20
      of response to single-agent irinotecan range from<SUP> </SUP>0% to =
17%,=20
      the 6-month PFS rates are consistently less than<SUP> </SUP>20%, =
and=20
      median survival is less than 12 weeks.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R3">3</A>-<A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R6">6</A></SUP>=20
      The reasons<SUP> </SUP>for the improved efficacy with the =
combination of=20
      irinotecan<SUP> </SUP>and bevacizumab are unclear. There are a =
number of=20
      potential<SUP> </SUP>mechanisms to explain the results, two of =
which may=20
      be particularly<SUP> </SUP>important. GBM is similar to other =
tumors, with=20
      a stem-like<SUP> </SUP>cell compartment as well as more =
differentiated=20
      tumor cells.<SUP> </SUP>Chemotherapy may be active against more=20
      differentiated cells<SUP> </SUP>but may not affect the tumor stem=20
      cells.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R28">28</A></SUP>=20
      Recently, Bao et<SUP> </SUP>al<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R29">29</A></SUP>=20
      demonstrated that bevacizumab suppresses the proangiogenic<SUP>=20
      </SUP>effect of glioma stem cells derived from human =
glioblastoma<SUP>=20
      </SUP>tumors and xenografts. Therefore, the combination of=20
      bevacizumab<SUP> </SUP>and irinotecan would treat both cellular=20
      compartments, the glioma<SUP> </SUP>stem cells and the more =
differentiated=20
      cells.<SUP> </SUP>
      <P>Another potential mechanism is normalization of the tumor=20
      vasculature<SUP> </SUP>as proposed by Jain et al.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R30">30</A>-<A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R32">32</A></SUP>=20
      Tumor angiogenesis produces<SUP> </SUP>abnormal vessels with =
increased=20
      tortuosity. The resultant high<SUP> </SUP>interstitial pressure =
produces=20
      hypoxia and a growth advantage<SUP> </SUP>for tumor cells.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R30">30</A></SUP>=20
      In addition, the elevated interstitial pressure<SUP> </SUP>limits=20
      perfusion of chemotherapeutic agents to the tumor cells.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R31">31</A></SUP><SUP>=20
      </SUP>Also, chemotherapeutic agents and radiation therapy are =
not<SUP>=20
      </SUP>as effective in areas of hypoxia.<SUP><A=20
      =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#R32">32</A></SUP>=20
      In summary, the efficacy<SUP> </SUP>seen with the combination of=20
      bevacizumab and irinotecan could<SUP> </SUP>be explained by an =
antitumor=20
      stem-cell effect by bevacizumab<SUP> </SUP>and an =
anti=96differentiated=20
      glioma tumor cell effect by<SUP> </SUP>irinotecan, as well as=20
      normalization of tumor vasculature, resulting<SUP> </SUP>in =
decreased=20
      interstitial pressure, less hypoxia, and increased<SUP> =
</SUP>delivery of=20
      irinotecan to the tumor.<SUP> </SUP>
      <P>In conclusion, the combination of bevacizumab and =
irinotecan<SUP>=20
      </SUP>was strikingly active against recurrent GBM. The toxicity =
was<SUP>=20
      </SUP>significant but acceptable, given the extremely poor =
prognosis<SUP>=20
      </SUP>of recurrent GBM. Further studies are needed to optimize =
the<SUP>=20
      </SUP>use of bevacizumab in glioblastoma patients and further =
improve<SUP>=20
      </SUP>their survival. A phase II randomized trial of bevacizumab=20
      alone<SUP> </SUP>versus bevacizumab and irinotecan in recurrent =
GBM is=20
      ongoing.<SUP> </SUP>The addition of bevacizumab to the initial =
treatment=20
      of GBM<SUP> </SUP>patients may have the greatest impact on =
improving=20
      survival.<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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>DISCUSSION<BR></A><IMG height=3D9 alt=3D" " =
hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/dot.gif" width=3D11 =

            border=3D0><FONT color=3D#464c53>AUTHORS' DISCLOSURES =
OF...</FONT><BR><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            border=3D0>AUTHOR CONTRIBUTIONS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
B>Employment=20
      or Leadership Position:</B> None <B>Consultant or Advisory<SUP>=20
      </SUP>Role:</B> Jennifer A. Quinn, Schering-Plough (C); Darell D.=20
      Bigner,<SUP> </SUP>Bradmer Pharmaceuticals (C), Celldex (C), Five =
Prime=20
      Therapeutics<SUP> </SUP>(C) <B>Stock Ownership:</B> David A. =
Reardon,=20
      Genentech; Darell D.<SUP> </SUP>Bigner, Bradmer Pharmaceuticals, =
Five=20
      Prime Therapeutics <B>Honoraria:</B><SUP> </SUP>Henry S. Friedman, =

      Genentech <B>Research Funding:</B> Henry S. Friedman,<SUP> =
</SUP>Genentech=20
      <B>Expert Testimony:</B> None <B>Other Remuneration:</B> None<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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.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://jco.ascopubs.org/icons/toc/dot.gif" =
width=3D11=20
            border=3D0><FONT color=3D#464c53>AUTHOR =
CONTRIBUTIONS</FONT><BR><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#BIBL"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/darrow.gif" =
width=3D11=20
            =
border=3D0>REFERENCES<BR></A></FONT></TH></TR></TBODY></TABLE>&nbsp;<BR><=
B>Conception=20
      and design:</B> James J. Vredenburgh, James E. Herndon<SUP> =
</SUP>II,=20
      David A. Reardon, Jeremy N. Rich, John Sampson, Darell D.<SUP>=20
      </SUP>Bigner, Henry S. Friedman<SUP> </SUP>
      <P><B>Financial support:</B> Darell D. Bigner<SUP> </SUP>
      <P><B>Administrative support:</B> James J. Vredenburgh, Melissa=20
      Wagner,<SUP> </SUP>Leighann Bailey, Darell D. Bigner, Henry S.=20
      Friedman<SUP> </SUP>
      <P><B>Provision of study materials or patients:</B> James J.=20
      Vredenburgh,<SUP> </SUP>Annick Desjardins, David A. Reardon, =
Jennifer A.=20
      Quinn, Jeremy<SUP> </SUP>N. Rich, Sith Sathornsumetee, John =
Sampson, Allan=20
      H. Friedman,<SUP> </SUP>Henry S. Friedman<SUP> </SUP>
      <P><B>Collection and assembly of data:</B> James J. Vredenburgh,=20
      Annick<SUP> </SUP>Desjardins, David A. Reardon, Jennifer A. Quinn, =
Jeremy=20
      N. Rich,<SUP> </SUP>Sith Sathornsumetee, John Sampson, Melissa =
Wagner,=20
      Leighann<SUP> </SUP>Bailey<SUP> </SUP>
      <P><B>Data analysis and interpretation:</B> James J. Vredenburgh,=20
      James<SUP> </SUP>E. Herndon II, Jennifer Marcello, David A. =
Reardon,=20
      Jeremy N.<SUP> </SUP>Rich, Allan H. Friedman, Henry S. =
Friedman<SUP>=20
</SUP>
      <P><B>Manuscript writing:</B> James J. Vredenburgh, James E. =
Herndon=20
      II,<SUP> </SUP>David A. Reardon, Sridharan Gururangan, Darell D. =
Bigner,=20
      Henry<SUP> </SUP>S. Friedman<SUP> </SUP>
      <P><B>Final approval of manuscript:</B> James J. Vredenburgh, =
Annick=20
      Desjardins,<SUP> </SUP>James E. Herndon II, David A. Reardon, =
Jeremy N.=20
      Rich, Sith<SUP> </SUP>Sathornsumetee, Sridharan Gururangan, John =
Sampson,=20
      Darell D.<SUP> </SUP>Bigner, Allan H. Friedman, Henry S. =
Friedman<SUP>=20
      </SUP>
      <P><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://jco.ascopubs.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 Grants No. 5 P50 CA108786, =
5 P50=20
      NS20023, and 4<SUP> </SUP>R37 CA11898 from the National Institutes =
of=20
      Health, Department<SUP> </SUP>of Health and Human Services, =
Bethesda, MD;=20
      the Preston Robert<SUP> </SUP>Tisch Brain Tumor Research Fund; and =
the=20
      Bryan Cless Research<SUP> </SUP>Fund. J.N.R. is a Damon =
Runyon-Lilly=20
      Clinical Investigator.<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://jco.ascopubs.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://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#top"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>TOP<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#ABS"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>ABSTRACT<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC1"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>INTRODUCTION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC2"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>PATIENTS AND METHODS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC3"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>RESULTS<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC4"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>DISCUSSION<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC5"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.org/icons/toc/uarrow.gif" =
width=3D11=20
            border=3D0>AUTHORS' DISCLOSURES OF...<BR></A><A=20
            =
href=3D"http://jco.ascopubs.org/cgi/content/full/25/30/4722?ijkey=3D93545=
6f31d91a541d93ec2fb650c6055d290408a#SEC6"><IMG=20
            height=3D9 alt=3D" " hspace=3D5=20
            src=3D"http://jco.ascopubs.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://jco.ascopubs.org/icons/toc/dot.gif" width=3D11 =

            border=3D0><FONT=20
        =
color=3D#464c53>REFERENCES</FONT><BR></FONT></TH></TR></TBODY></TABLE>&nb=
sp;<BR>
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      April 20, 2007; accepted June 20, 2007.
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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_0000_01C814A3.7C962AA0
Content-Type: application/octet-stream
Content-Transfer-Encoding: quoted-printable
Content-Location: http://jco.ascopubs.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_0000_01C814A3.7C962AA0
Content-Type: application/octet-stream
Content-Transfer-Encoding: quoted-printable
Content-Location: http://jco.ascopubs.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=
          e.style.backgroundAttachment =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-color") {=0A=
          e.style.backgroundColor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-image") {=0A=
          e.style.backgroundImage =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-position") {=0A=
          e.style.backgroundPosition =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-position-x") {=0A=
          e.style.backgroundPositionX =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-position-y") {=0A=
          e.style.backgroundPositionY =3D value;=0A=
        }=0A=
        else if (name =3D=3D "background-repeat") {=0A=
          e.style.backgroundRepeat =3D value;=0A=
        }=0A=
        else if (name =3D=3D "behavior") {=0A=
          e.style.behavior =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border") {=0A=
          e.style.border =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-bottom") {=0A=
          e.style.borderBottom =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-bottom-color") {=0A=
          e.style.borderBottomColor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-bottom-style") {=0A=
          e.style.borderBottomStyle =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-bottom-width") {=0A=
          e.style.borderBottomWidth =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-collapse") {=0A=
          e.style.borderCollapse =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-color") {=0A=
          e.style.borderColor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-left") {=0A=
          e.style.borderLeft =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-left-color") {=0A=
          e.style.borderLeftColor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-left-style") {=0A=
          e.style.borderLeftStyle =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-left-width") {=0A=
          e.style.borderLeftWidth =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-right") {=0A=
          e.style.borderRight =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-right-color") {=0A=
          e.style.borderRightColor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-right-style") {=0A=
          e.style.borderRightStyle =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-right-width") {=0A=
          e.style.borderRightWidth =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-style") {=0A=
          e.style.borderStyle =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-top") {=0A=
          e.style.borderTop =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-top-color") {=0A=
          e.style.borderTopColor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-top-style") {=0A=
          e.style.borderTopStyle =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-top-width") {=0A=
          e.style.borderTopWidth =3D value;=0A=
        }=0A=
        else if (name =3D=3D "border-width") {=0A=
          e.style.borderWidth =3D value;=0A=
        }=0A=
        else if (name =3D=3D "bottom") {=0A=
          e.style.bottom =3D value;=0A=
        }=0A=
        else if (name =3D=3D "clear") {=0A=
          e.style.clear =3D value;=0A=
        }=0A=
        else if (name =3D=3D "clip") {=0A=
          e.style.clip =3D value;=0A=
        }=0A=
        else if (name =3D=3D "color") {=0A=
          e.style.color =3D value;=0A=
        }=0A=
        else if (name =3D=3D "cssText") {=0A=
          e.style.Sets =3D value;=0A=
        }=0A=
        else if (name =3D=3D "cursor") {=0A=
          e.style.cursor =3D value;=0A=
        }=0A=
        else if (name =3D=3D "direction") {=0A=
          e.style.direction =3D value;=0A=
        }=0A=
        else if (name =3D=3D "display") {=0A=
          e.style.display =3D value;=0A=
        }=0A=
        else if (name =3D=3D "font") {=0A=
          e.style.font =3D value;=0A=
        }=0A=
        else if (name =3D=3D "font-family") {=0A=
          e.style.fontFamily =3D value;=0A=
        }=0A=
        else if (name =3D=3D "font-size") {=0A=
          e.style.fontSize =3D value;=0A=
        }=0A=
        else if (name =3D=3D "font-style") {=0A=
          e.style.fontStyle =3D value;=0A=
        }=0A=
        else if (name =3D=3D "font-variant") {=0A=
          e.style.fontVariant =3D value;=0A=
        }=0A=
        else if (name =3D=3D "font-weight") {=0A=
          e.style.fontWeight =3D value;=0A=
        }=0A=
        else if (name =3D=3D "height") {=0A=
          e.style.height =3D value;=0A=
        }=0A=
        else if (name =3D=3D "ime-mode") {=0A=
          e.style.imeMode =3D value;=0A=
        }=0A=
        else if (name =3D=3D "layout-flow") {=0A=
          e.style.layoutFlow =3D value;=0A=
        }=0A=
        else if (name =3D=3D "layout-grid") {=0A=
          e.style.layoutGrid =3D value;=0A=
        }=0A=
        else if (name =3D=3D "layout-grid-char") {=0A=
          e.style.layoutGridChar =3D value;=0A=
        }=0A=
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}=0A=

------=_NextPart_000_0000_01C814A3.7C962AA0
Content-Type: application/octet-stream
Content-Transfer-Encoding: quoted-printable
Content-Location: http://jco.ascopubs.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=
    if (appname =3D=3D "Microsoft Internet Explorer") {=0A=
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        var v =3D parseFloat(userAgent.substring(n+s.length));=0A=
        if (v < 6) {=0A=
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        }=0A=
      }=0A=
    }=0A=
  }=0A=
=0A=
  /*=0A=
   * Acquire table row element to update, initiate callback=0A=
   * to update table with Entrez Links.=0A=
   */=0A=
  var tr =3D document.getElementById('entrez_callback_'+pmid);=0A=
  if (!tr) {=0A=
    return;=0A=
  }=0A=
  var req =3D new XMLHttpRequest();=0A=
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    return;=0A=
  }=0A=
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=3D=3D 304)) {=0A=
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      }=0A=
      var tbl =3D tr.parentNode;=0A=
      tbl.replaceChild(dst, tr);=0A=
    }=0A=
  }=0A=
  req.open('GET', callback_url, true);=0A=
  req.send(null);=0A=
}=0A=

------=_NextPart_000_0000_01C814A3.7C962AA0--

