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    <TD>Child's Nervous System</TD></TR>
  <TR>
    <TD>=A9&nbsp;Springer-Verlag&nbsp;2007</TD></TR>
  <TR>
    <TD>10.1007/s00381-007-0538-8</TD></TR></TBODY></TABLE><!--Begin =
Abstract-->
<H2 class=3Drubric>Original Paper</H2>
<DIV class=3DHeading1><A name=3Dtitle></A>Intrathecal chemotherapy for =
refractory=20
disseminated medulloblastoma </DIV>
<P class=3DAuthorGroup>Junichi&nbsp;Yoshimura<SUP>1&nbsp;<A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#ContactOfAuthor1"><IMG=20
alt=3D"Contact Information"=20
src=3D"http://www.springerlink.com/content/m430363066614837/contact.gif" =

border=3D0></A></SUP>, Kenichi&nbsp;Nishiyama<SUP>1</SUP>,=20
Hiroshi&nbsp;Mori<SUP>2</SUP>, Hideaki&nbsp;Takahashi<SUP>1</SUP> and=20
Yukihiko&nbsp;Fujii<SUP>1</SUP></P>
<TABLE>
  <TBODY>
  <TR vAlign=3Dtop>
    <TD><SPAN class=3DAffiliation><A =
name=3DAff1></A>(1)&nbsp;</SPAN></TD>
    <TD><SPAN class=3DAffiliation>Department of Neurosurgery, Brain =
Research=20
      Institute, University of Niigata, 1-757 Asahimachi, Niigata=20
      City&nbsp;951-8585, Japan</SPAN></TD></TR></TBODY></TABLE>
<TABLE>
  <TBODY>
  <TR vAlign=3Dtop>
    <TD><SPAN class=3DAffiliation><A =
name=3DAff2></A>(2)&nbsp;</SPAN></TD>
    <TD><SPAN class=3DAffiliation>Division of Pediatric Neurosurgery, =
Jikei=20
      University Hospital, Jikei Women=92s and Children=92s Medical =
Center,=20
      Minato-ku, Tokyo, Japan</SPAN></TD></TR></TBODY></TABLE>
<P><A name=3DContactOfAuthor1></A></P>
<TABLE class=3DContact>
  <TBODY>
  <TR>
    <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20
      =
src=3D"http://www.springerlink.com/content/m430363066614837/contact.gif" =

      border=3D0></TD>
    =
<TD><STRONG>Junichi&nbsp;</STRONG><STRONG>Yoshimura</STRONG><STRONG></STR=
ONG><BR><STRONG>Email:=20
      </STRONG><A=20
      =
href=3D"mailto:junyoshi@bri.niigata-u.ac.jp">junyoshi@bri.niigata-u.ac.jp=
</A></TD></TR></TBODY></TABLE>
<P class=3DAffiliation><STRONG>Received:=20
</STRONG>27&nbsp;March&nbsp;2007&nbsp;&nbsp;<STRONG>Revised:=20
</STRONG>4&nbsp;September&nbsp;2007&nbsp;&nbsp;<STRONG>Published online: =

</STRONG>5&nbsp;December&nbsp;2007 </P>
<DIV class=3DAbstract><A name=3DAbs1></A><SPAN =
class=3DAbstractHeading>Abstract</SPAN>
<DIV class=3DAbstractSection>
<DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20
name=3DASec1></A>Objective&nbsp;&nbsp;</SPAN>To analyze the effect of =
intrathecal=20
(IT) chemotherapy for disseminated medulloblastoma. </DIV></DIV>
<DIV class=3DAbstractSection>
<DIV class=3D""><SPAN class=3DAbstractSectionHeading><A =
name=3DASec2></A>Materials and=20
methods&nbsp;&nbsp;</SPAN>Twenty-one patients received IT chemotherapy =
using the=20
chemotherapeutic agents of methotrexate (MTX) and nitrosoureas (ACNU, =
MCNU)=20
including nine patients for residual leptomeningeal lesions after =
initial=20
surgery and radiation, and 12 for a recurrence with leptomeningeal=20
dissemination. Of these 21 patients, 12 received a lumbar and/or =
ventricular=20
bolus injection of the chemotherapeutic agents, one received the=20
ventriculolumbar perfusion of the agents, and eight received both the =
perfusion=20
and bolus injection. The doses ranged from 6=967&nbsp;mg/m<SUP>2</SUP> =
of ACNU for=20
perfusion and 3=963.5&nbsp;mg/m<SUP>2</SUP> of ACNU, MCNU, or MTX for =
the bolus=20
injection, and the cycles were administered from 3 to 12 times for =
perfusion and=20
from 5 to 54 times for the bolus injection. The effects of chemotherapy =
were=20
assessed by both radiological and cytological examinations, and the =
clinical=20
symptoms were also assessed. Radiological and/or cytological responses =
were=20
observed in 10 of 21 patients (47.6%), including seven cases =
demonstrating a=20
complete remission. The 5-year overall survival rate and 5-year survival =
rate=20
after dissemination were 61.5 and 46.4%, respectively. Five patients who =

received a lumbar bolus injection of nitrosoureas experienced paraplegia =
and=20
double incontinence. One patient who received a ventricular injection of =

nitrosoureas experienced truncal ataxia. </DIV></DIV>
<DIV class=3DAbstractSection>
<DIV class=3D""><SPAN class=3DAbstractSectionHeading><A=20
name=3DASec3></A>Conclusion&nbsp;&nbsp;</SPAN>IT chemotherapy was found =
to be=20
effective in some cases with refractory disseminated medulloblastoma and =
it=20
seems to be an appropriate treatment choice for leptomeningeal =
recurrence.=20
However, the frequent bolus injections of nitrosoureas should be avoided =
to=20
prevent the side effects. </DIV></DIV></DIV>
<P class=3DKeyword><SPAN=20
class=3DKeywordHeading>Keywords&nbsp;&nbsp;</SPAN>Medulloblastoma&nbsp;-&=
nbsp;Dissemination&nbsp;-&nbsp;Intrathecal=20
(IT) chemotherapy&nbsp;-&nbsp;Ventriculolumbar perfusion=20
chemotherapy&nbsp;-&nbsp;Nitrosourea=20
(ACNU&nbsp;-&nbsp;MCNU)&nbsp;-&nbsp;Methotrexate </P>
<DIV class=3D""><A name=3DSec1></A>
<HR>

<DIV class=3Dheading2>Introduction</DIV>
<P class=3D"">Treatment for recurrent medulloblastoma with =
leptomeningeal=20
dissemination is very difficult and the prognosis of such refractory=20
medulloblastoma patients tends to be extremely poor. No definitive =
treatment=20
strategy has yet been established and we therefore usually choose =
high-dose=20
chemotherapy, intrathecal (IT) chemotherapy [<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR1">1</A></CITE>=96<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR11">11</A></CITE>],=20
or additional radiotherapy depending on each individual case. As a =
standard=20
procedure for medulloblastoma at our institute, craniospinal irradiation =
is=20
performed as soon as possible after the maximum possible removal of the =
primary=20
tumor. After these initial therapies, maintenance systemic chemotherapy =
using PE=20
(CBDCA, VP-16) or ICE (IFOS, CDDP, VP-16) regimen is thereafter =
performed for=20
about 2&nbsp;years. During the course of these therapies, we have also =
performed=20
IT chemotherapy aggressively for advanced stage disseminated =
medulloblastomas,=20
such as leptomeningeal recurrences or residual leptomeningeal lesions =
since=20
1979. In this study, we retrospectively analyzed the clinical data for =
patients=20
with IT chemotherapy to evaluate the effectiveness of this unique =
adjuvant=20
therapeutic option for disseminated medulloblastoma. </P></DIV>
<DIV class=3D""><A name=3DSec2></A>
<HR>

<DIV class=3Dheading2>Materials and methods</DIV>
<DIV class=3D""><A name=3DSec3></A>
<DIV class=3DHeading3>Patients</DIV>
<P class=3D"">From 1979 to 2005, 45 patients with medulloblastoma were =
treated=20
with craniospinal irradiation and maintenance systemic chemotherapy =
after a=20
surgical removal of the primary tumor. Of these 45 patients, 21 received =
IT=20
chemotherapy including nine patients for residual leptomeningeal lesions =
after=20
the initial surgery and radiation, and 12 patients for leptomeningeal =
recurrence=20
after a complete remission. The patients included 14 males and 7 =
females. The=20
patients ranged in age from 1 to 26&nbsp;years (mean 10.9&nbsp;years =
old). The=20
interval between the diagnosis of the primary disease and the detection =
of the=20
subarachnoid dissemination in cases of leptomeningeal recurrence ranged =
from 6=20
to 80&nbsp;months (26&nbsp;months of average). The primary tumors were =
confirmed=20
to be medulloblastoma in all 21 patients based on a histopathological =
diagnosis.=20
The diagnosis of subarachnoid dissemination was made based on =
cerebrospinal=20
fluid (CSF) cytology, computed tomography and/or magnetic resonance =
imaging=20
(MRI). The IT chemotherapeutic regimen was carefully explained to the =
patients=20
and/or their family, and informed consent was obtained from all =
participating=20
patients. </P>
<DIV class=3DPara>
<DIV class=3D"">Of these 21 patients, 12 patients received a lumbar and=20
ventricular bolus injection of the chemotherapeutic agents, one received =

ventriculolumbar perfusion of the agents, while eight received both the=20
perfusion and the bolus injection. Systemic chemotherapy was combined in =
17=20
cases while additional radiotherapy was combined in eight cases. The =
cycles=20
ranged from 3 to 12 times for perfusion and from 5 to 54 times for the =
bolus=20
injection (Table&nbsp;<A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#Tab1">1</A>).=20
All these data were obtained from the patients=92 records. <A =
name=3DTab1></A>
<DIV class=3DCapt><SPAN =
class=3DCaptNr>Table&nbsp;1&nbsp;</SPAN>Intrathecal (IT)=20
chemotherapeutic regimens of the 21 patients with disseminated =
medulloblastoma=20
</DIV>
<TABLE border=3D1>
  <COLGROUP>
  <COL align=3Dleft>
  <COL align=3Dleft></COLGROUP>
  <THEAD>
  <TR class=3Dheader>
    <TH align=3Dleft>
      <P class=3D"">Number of patients (<I>n</I>&#8201;=3D&#8201;21) =
</P></TH>
    <TH align=3Dleft>
      <P class=3D"">IT Cx with systemic Cx (PE or ICE =
Cx)</P></TH></TR></THEAD>
  <TBODY>
  <TR class=3Dnoclass>
    <TD align=3Dleft>
      <P class=3D"">12</P></TD>
    <TD align=3Dleft>
      <P class=3D"">Lumbar and/or ventricular bolus =
injection</P></TD></TR>
  <TR class=3Dnoclass>
    <TD align=3Dleft>
      <P class=3D"">1</P></TD>
    <TD align=3Dleft>
      <P class=3D"">Ventriculolumbar perfusion</P></TD></TR>
  <TR class=3Dnoclass>
    <TD align=3Dleft>
      <P class=3D"">8</P></TD>
    <TD align=3Dleft>
      <P class=3D"">Perfusion and bolus =
injection</P></TD></TR></TBODY></TABLE>
<DIV class=3DCapt>
<DIV class=3DCaptCont>
<DIV class=3D"">Drug: ACNU/MCNU, MTX; dose: 6=967&nbsp;mg/m<SUP>2</SUP> =
(perfusion),=20
3=963.5&nbsp;mg/m<SUP>2</SUP> (bolus injection); cycle: 3=9612 times =
(perfusion),=20
5=9654 times (bolus injection) </DIV></DIV>
<DIV class=3DCaptCont>
<DIV class=3D""><I>Cx</I> Chemotherapy, <I>PE</I> CBDCA + VP-16, =
<I>ICE</I> IFOS +=20
CDDP + VP-16 </DIV></DIV></DIV></DIV></DIV></DIV>
<DIV class=3D""><A name=3DSec4></A>
<DIV class=3DHeading3>Treatment</DIV>
<DIV class=3DPara>
<DIV class=3D"">All patients had Ommaya=92s reservoirs established on =
one side of=20
the lateral ventricle and the lumbar spinal canal beforehand. Before the =
start=20
of the perfusion chemotherapy, the communication between the ventricular =
system=20
and the subarachnoid space was anatomically confirmed by MRI and shunted =
cases=20
did not receive this perfusion chemotherapy. On the other hand, in the =
previous=20
shunted cases of the bolus injection, after drug administration, either =
the=20
on=96off valve was occluded or the adjustable valve was set to the =
highest=20
pressure for several hours and then it was re-opened.=20
<TABLE class=3DOrderedList>
  <TBODY>
  <TR vAlign=3Dtop>
    <TD>1.&nbsp;</TD>
    <TD><I>Perfusion chemotherapy</I>=20
      <DIV class=3DListPara>
      <DIV class=3D"">The patients lay in a lateral position and=20
      6=967&nbsp;mg/m<SUP>2</SUP> of=20
      =
ACNU(3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitr=
osourea=20
      hydrochloride, nimustine) dissolved in 100&nbsp;ml of lactated =
Ringer with=20
      0.4&nbsp;ml of 7.0% sodium bicarbonate and 10&nbsp;mg of =
prednisolone=20
      (PSL) was drip infused into the ventricular reservoir and drained =
via the=20
      reservoir placed in the lumbar region at approximately the same =
rate as=20
      that of the infusion for about 60&nbsp;min. Thereafter, the =
patients=20
      remained in a recumbent position for about 1&nbsp;h before =
returning home.=20
      The perfusion was scheduled every 1 or 2&nbsp;weeks on an =
outpatient=20
      basis. </DIV></DIV></TD></TR>
  <TR vAlign=3Dtop>
    <TD>2.&nbsp;</TD>
    <TD><I>Bolus injection</I>=20
      <DIV class=3DListPara>
      <DIV class=3D"">The patients were placed in a lateral position and =
after=20
      removing an equivalent volume of CSF (approximately 4&nbsp;ml) =
from each=20
      ventricle and the lumbar reservoirs, 3=963.5&nbsp;mg/m<SUP>2</SUP> =
of ACNU,=20
      MCNU (methyl =
6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-&#945;-<SPAN=20
      style=3D"FONT-VARIANT: =
small-caps"><SMALL>d</SMALL></SPAN>-glucopyranoside,=20
      ranimustine) or MTX with 6=967&nbsp;mg/m<SUP>2</SUP> of PSL =
dissolved in=20
      2&nbsp;ml of normal saline (NS) was bolus injected via Ommaya=92s =
reservoir=20
      of the lateral ventricle and the lumbar region and then it was =
flushed=20
      with 2&nbsp;ml of NS. Next, the patients laid down flat in the =
supine=20
      position for about 1&nbsp;h before returning home. The bolus =
injection was=20
      scheduled every 1 or 2&nbsp;weeks on an outpatient basis.=20
  </DIV></DIV></TD></TR></TBODY></TABLE></DIV></DIV></DIV>
<DIV class=3D""><A name=3DSec5></A>
<DIV class=3DHeading3>Evaluation and response criteria</DIV>
<P class=3D"">The effects of the chemotherapy were assessed by cranial =
and spinal=20
MRI and CSF cytology, and also clinical symptoms were evaluated. A =
complete=20
response (CR) was defined as the complete clearing of radiographic =
disease, and=20
the malignant cells disappeared from the CSF. A partial response (PR) =
was=20
defined as an improvement in the CSF findings and/or the =
neuroradiological=20
findings. Where none of the parameters showed any change or showed =
changes for=20
the worse, a classification of no change (NC) or progressive disease =
(PD) was=20
assigned, respectively. The patients who showed CR or PR were considered =
to be=20
responders when calculating the response rates. The survival rates were=20
estimated by the Kaplan=96Meier method. In this study, 18 of those 21 =
patients=20
underwent MRI before and after IT chemotherapy and 11 of those 21 =
underwent CSF=20
cytology before and after IT chemotherapy. </P></DIV></DIV>
<DIV class=3D""><A name=3DSec6></A>
<HR>

<DIV class=3Dheading2>Results</DIV>
<DIV class=3D""><A name=3DSec7></A>
<DIV class=3DHeading3>Response rate</DIV>
<DIV class=3DPara>
<DIV class=3D"">The radiological and/or cytological responses were =
observed in 10=20
of the 21 patients (47.6%) including seven who demonstrated a complete=20
remission. Seven of 18 patients who underwent MRI showed an improvement. =
They=20
included four complete responses and three partial responses. Six of the =
11=20
cases evaluated by CSF cytology achieved a clearance of malignant cells. =
The=20
estimated 5-year overall survival rate after the diagnosis of primary =
tumor was=20
61.5% and 1-, 2-, and 5-year survival rates after the diagnosis of =
dissemination=20
were 81.0, 61.9, and 46.4%, respectively (Fig.&nbsp;<A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#Fig1">1</A>).=20
The mean follow-up period of surviving patients was 11.4&nbsp;years =
(range=20
through 4.0 to 23.0&nbsp;years).=20
<DIV class=3DFigure><A name=3DFig1></A><IMG=20
alt=3DMediaObjects/381_2007_538_Fig1_HTML.gif=20
src=3D"http://www.springerlink.com/content/m430363066614837/MediaObjects/=
381_2007_538_Fig1_HTML.gif"></DIV>
<DIV class=3DCapt><SPAN =
class=3DCaptNr>Fig.&nbsp;1&nbsp;</SPAN>Kaplan=96Meier survival=20
curves showing the overall survival (<I>solid line</I>) and survival =
after=20
dissemination (<I>dotted line</I>) </DIV>
<HR>
</DIV></DIV></DIV>
<DIV class=3D""><A name=3DSec8></A>
<DIV class=3DHeading3>Representative cases</DIV>
<DIV class=3DPara>
<DIV class=3D"">The patient was a 12-year-old girl. The MRI of onset =
showed=20
scattered spinal dissemination, whose initial Chang=92s stage was M3. =
After a=20
surgical removal of the primary tumor and craniospinal irradiation, a =
complete=20
remission was achieved. However, 2&nbsp;years later, during the =
maintenance=20
chemotherapy, spinal leptomeningeal dissemination recurred. =
Consequently, the=20
patient received 10 courses of ACNU perfusion with systemic chemotherapy =
for=20
about 5&nbsp;months and a complete response was thus achieved according =
to both=20
the MRI an cytological findings (Fig.&nbsp;<A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#Fig2">2</A>,=20
case 1:a=96e).=20
<DIV class=3DFigure><A name=3DFig2></A><IMG=20
alt=3DMediaObjects/381_2007_538_Fig2_HTML.gif=20
src=3D"http://www.springerlink.com/content/m430363066614837/MediaObjects/=
381_2007_538_Fig2_HTML.gif"></DIV>
<DIV class=3DCapt><SPAN class=3DCaptNr>Fig.&nbsp;2&nbsp;</SPAN>MRI scans =
showing the=20
effects of IT chemotherapy. Case 1 <B>a</B> MRI of onset, <B>b</B> after =
the=20
initial surgery and CSI, <B>c</B> leptomeningeal recurrence, <B>d</B> =
and=20
<B>e</B> pre- and post-IT chemotherapy </DIV>
<HR>
</DIV></DIV></DIV>
<DIV class=3D""><A name=3DSec9></A>
<DIV class=3DHeading3>Adverse events</DIV>
<P class=3D"">Five patients who received a lumbar bolus injection of =
nitrosoureas=20
more than seven times experienced paraplegia and double incontinence. =
One=20
patient with 54 administrations of ventricular injection of nitrosoureas =

experienced truncal ataxia. </P></DIV></DIV>
<DIV class=3D""><A name=3DSec10></A>
<HR>

<DIV class=3Dheading2>Discussion</DIV>
<P class=3D"">Leptomeningeal dissemination is a serious and fatal state =
of=20
malignant brain tumor and medulloblastoma frequently disseminates =
throughout the=20
cerebrospinal fluid. The treatment of leptomeningeal dissemination of =
the=20
medulloblastoma is very difficult and leptomeningeal recurrence is the =
most=20
serious of all these conditions. Major treatments of leptomeningeal=20
dissemination are craniospinal irradiation (CSI) including radiosurgery, =

systemic chemotherapy including high-dose chemotherapy with autologous =
bone=20
marrow transplantation and intrathecal (IT) chemotherapy [<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR1">1</A></CITE>=96<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR11">11</A></CITE>].=20
Medulloblastoma is a radiosensitive tumor, and irradiation is therefore=20
considered to be an appropriate and effective treatment modality, but =
almost all=20
patients had already undergone CSI as the initial therapy, as a result, =
the=20
additional irradiated dose and fields are strictly limited because of =
the risk=20
of radiation necrosis of the nervous tissue. Additional radiotherapy is =
usually=20
limited to the palliative care of pain control or for temporary rescue =
in a case=20
in which the long-term outcome is beyond consideration. On the other =
hand, we=20
consider radiosurgery, such as the gamma knife, to be also useful for =
treating=20
nodular intracranial disseminations, but it is an insufficient treatment =
for=20
widespread CSF dissemination. </P>
<P class=3D"">Systemic chemotherapy is necessary for the treatment of=20
medulloblastoma and sometimes minute disseminations disappear as a =
result of=20
conventional systemic chemotherapy, but sufficient drug delivery is not =
achieved=20
across the blood-brain barrier. High-dose chemotherapy with bone marrow=20
transplantation using peripheral blood stem cells is sometimes =
performed, but=20
this method is usually performed one or two times because of limitations =
in=20
collecting stem cells and after high-dose chemotherapy, maintenance =
systemic=20
chemotherapy cannot be performed in most cases because of persistent=20
myelosuppression. If high-dose chemotherapy does not eradicate the =
disseminated=20
lesions, then a patient enters a lethal state due to a regrowth of the =
tumor;=20
therefore, the indications for high-dose chemotherapy to treat =
leptomeningeal=20
recurrence thus remain controversial. </P>
<P class=3D"">IT chemotherapy is convenient, repeatable, and there are =
no systemic=20
side effects such as myelosuppression. Theoretically, drug delivery is =
achieved=20
for whole leptomeningeal lesions; therefore, IT chemotherapy appears to =
be the=20
treatment of choice for such patients. Unfortunately, the effect of =
conventional=20
IT chemotherapy with MTX, cytosine arabinoside, and thio-TEPA is thought =
to only=20
be temporary [<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR2">2</A></CITE>,=20
<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR5">5</A></CITE>,=20
<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR6">6</A></CITE>,=20
<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR8">8</A></CITE>,=20
<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR9">9</A></CITE>],=20
and there has so far been no large clinical study, and thus the effect =
of IT=20
chemotherapy has not been established. On the other hand, one clinical =
study=20
produced an 88% response rate by ACNU perfusion for disseminated =
medulloblastoma=20
and PNET [<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR10">10</A></CITE>].=20
Another study of IT chemotherapy of Mafosfamide, a cyclophosphamide =
derivative,=20
reported a 70% response rate [<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR7">7</A></CITE>].=20
In our study, about 50% of patients showed a clinical response. Seven =
patients=20
achieved a complete remission and survived for a long time, and the =
5-year=20
survival rate after dissemination was 46.4%. The prognosis of the =
patients with=20
disseminated medulloblastoma of noncomplete remission after initial =
treatment=20
and leptomeningeal recurrence is thought to be extremely poor. IT =
chemotherapy=20
thus appears to be the treatment of choice for disseminated =
medulloblastoma.=20
However, we have to pay attention to some difficult points when =
performing IT=20
chemotherapy. At first, the combination of systemic chemotherapy is =
necessary=20
because IT chemotherapy probably provides insufficient drug delivery =
into deep=20
parenchymal invading lesions, and thus both the intrathecal-side and=20
parenchymal-side drug delivery (like a sandwich) is needed for =
especially thick=20
bulky disseminated lesions. Second, there is the problem of how to =
achieve a=20
sufficient concentration of the drug in the subarachnoid space over the =
cerebral=20
convexities. Because in the ventriculolumbar perfusion method, the drug =
is=20
infused into the ventricle and it flows straight down the spinal =
subarachnoid=20
space and then drains through the lumbar reservoir, and thus the drug=20
concentration in the ventricle and spinal subarachnoid space is =
sufficient to=20
achieve an appropriate therapeutic effect [<CITE><A=20
href=3D"http://www.springerlink.com/content/m430363066614837/fulltext.htm=
l#CR3">3</A></CITE>].=20
However, a sufficient retrograde drug flow from the cisterna magna to =
the=20
cerebral convexity is difficult to obtain using this perfusion method. =
On the=20
other hand, because of the short half-life of the nitrosoureas, a =
sufficient=20
concentration of the drug in the whole meningeal field cannot be =
achieved by the=20
bolus injection method. Therefore, another method is necessary to =
achieve a=20
sufficient concentration of nitrosoureas in the subarachnoid space over =
the=20
cerebral convexity. The other problem is myelotoxicity by a bolus =
injection of=20
nitrosoureas into the lumbar spinal canal. In our study, a bolus =
injection of=20
nitrosoureas (3=963.5&nbsp;mg/m<SUP>2</SUP>) every 1 or 2&nbsp;weeks and =
more than=20
seven times bolus injection caused permanent myelotoxicity of paraplegia =
and=20
double incontinence. Perfusion chemotherapy and up to 32 administrations =
of a=20
ventricular bolus injection of nitrosoureas did not cause any permanent=20
toxicity. In addition, a bolus injection of MTX into the ventricle and =
lumbar=20
spinal canal did not cause any toxicity. Therefore, the high =
concentration of=20
nitrosoureas in the lumbar spinal canal was thus considered to have =
caused=20
myelotoxicity. The failure of sufficient diffusion of the drug is also =
related=20
to the side effects because the myelotoxicity appeared in the lumbar or =
lower=20
segment of the spinal cord and did not appear in either the thoracic or =
higher=20
region. In addition, these patients received spinal irradiation of 24 to =

36&nbsp;Gy, so spinal radiation also can influence the susceptibility to =
such=20
myelotoxicity. Based on these findings, to reduce myelotoxicity, a lower =
drug=20
concentration can lessen the side effects because the concentration of =
perfusion=20
(0.1&nbsp;mg/ml) did not cause any toxicity. The Trendelenburg position =
after a=20
bolus injection can improve the diffusion of the drug because the =
specific=20
gravity of nitrosoureas (1.019; ACNU 5&nbsp;mg in NS 2&nbsp;ml) is =
heavier than=20
that of CSF (1.005=961.009). Further studies on the administration =
methods, drug=20
concentrations and drug combinations are thus necessary to prevent side =
effects.=20
Thus, from the view points of effectiveness and safety, ventriculolumbar =

perfusion, ventricular bolus injection, and several times of lumbar =
bolus=20
injection of nitrosoureas are appropriate IT chemotherapy for refractory =

disseminated medulloblastoma at present. </P></DIV>
<DIV class=3D""><A name=3DSec11></A>
<HR>

<DIV class=3Dheading2>Conclusion</DIV>
<P class=3D"">IT chemotherapy is therefore considered to be effective in =
some=20
cases with disseminated medulloblastoma and it thus seems to be an =
appropriate=20
treatment choice for leptomeningeal recurrence. However, the frequent =
lumbar=20
bolus injection of nitrosoureas should be avoided to prevent side =
effects.=20
Further studies are therefore warranted to establish more effective =
treatment=20
regimens. </P></DIV>
<P></P>
<HR>

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