10.1007/s11060-009-0040-0</TIT= LE> <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18852"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0040-0</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Case Report</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Intrathecal liposomal = cytarabine in=20 combination with temozolomide in low-grade oligoastrocytoma with = leptomeningeal=20 dissemination </DIV> <P class=3DAuthorGroup>Maria Grazia Passarin<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#ContactOfAuthor1"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/contact.gif">= </A></SUP>,=20 Giuseppe Moretto<SUP>2</SUP>, = Anna Maria Musso<SUP>2</SUP>,=20 Sarah Ottaviani<SUP>2</SUP>, Barbara Masotto<SUP>3</SUP>,=20 Claudio Ghimenton<SUP>4</SUP>, Paolo Iuzzolino<SUP>5</SUP>,=20 Ebba Buffone<SUP>1</SUP>, Roberta Rud=E0<SUP>6</SUP>,=20 Riccardo Soffietti<SUP>6</SUP>, Emanuela Vattemi<SUP>7</SUP> = and=20 Rebecca Pedersini<SUP>8</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neurology, USSL 22, Via = Ospedale=20 6, 37012 Bussolengo, Verona, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neurology, Azienda=20 Ospedaliera-Universitaria di Verona, Verona,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neurosurgery, Azienda=20 Ospedaliera-Universitaria di Verona, Verona,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Pathology, Azienda=20 Ospedaliera-Universitaria di Verona, Verona,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Pathology, Azienda = Ospedaliera di=20 Belluno, Belluno, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff6></A>(6) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neuro-Oncology, University = of=20 Torino, Torino, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Medical Oncology, Central=20 Hospital, Bolzano, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Spedali Civili, Brescia,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/contact.gif">= </TD> = <TD><STRONG>Maria </STRONG><STRONG>Grazia </STRONG><STRONG>Pass= arin</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:mariagraziapassarin@hotmail.it">mariagraziapassarin@hotmai= l.it</A></TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>3 August 2009 <STRONG>Accepted:=20 </STRONG>12 October 2009 <STRONG>Published online:=20 </STRONG>31 October 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>Leptomeningeal = dissemination of=20 low-grade gliomas is an uncommon event. A 43-year old male presented = with=20 dizziness, gait ataxia, and diplopia. A nonenhancing lesion in the right = cerebellar peduncle was identified, subtotally resected, and diagnosed = as a=20 grade II astrocytoma. After one year a nodular spread in the brain and=20 leptomeninges was diagnosed, so the patient started chemotherapy with=20 temozolomide and liposomal cytarabine. Complete remission was achieved = after=20 12 months of treatment and the patient is still free from the = disease after=20 a follow-up of 24 months. We suggest that this combination may be a = valuable treatment option. </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Leptomeningeal=20 carcinomatosis - Low-grade astrocytoma - Liposomal=20 cytarabine - Temozolomide </P> <DIV class=3DFulltext> <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P>Low-grade gliomas (LGG) are a group of relatively uncommon primary = brain=20 tumors, including astrocytomas, oligodendrogliomas, and mixed gliomas,=20 classified by the World Health Organization (WHO) grading system (2007) = as grade=20 2 lesions. The natural history of LGG shows great variability, and = optimum=20 disease management remains a challenge for the treating physician = [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR1">1</A></CITE>].=20 Leptomeningeal dissemination (LMD; also referred to as neoplastic = meningitis) is=20 a rare and serious complication of LGG. Current treatment of LMD is = designed to=20 improve or stabilize neurologic symptoms and to prolong survival. </P> <P>In this paper we report the case of a 43-year-old patient diagnosed = with LMD=20 from grade II oligoastrocytoma for whom complete remission was achieved = after=20 treatment with a sustained-release formulation of liposomal cytarabine = combined=20 with temozolomide. To the best of our knowledge, this is the first = report=20 describing long-lasting remission after treatment with this combination = in an=20 adult patient with LMD from low-grade oligoastrocytoma. </P></DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Case report</DIV> <DIV class=3DPara> <DIV>A 43-year-old male presented in July, 2005 with a five-month = history of=20 dizziness, gait ataxia, and intermittent diplopia. The patient had an=20 unremarkable medical history and no relevant family history of disease. = Magnetic=20 resonance imaging (MRI) revealed a nonenhancing lesion in the right = cerebellar=20 peduncle (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig1">1</A>).=20 The patient underwent surgery and partial resection of the tumor was = performed.=20 Histologic examination revealed a grade II astrocytoma (WHO) with an=20 oligodendroglial component (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig2">2</A>a),=20 and no 1p/19q co-deletion (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig2">2</A>b).=20 After surgery, the symptoms improved, therefore we considered it safe to = adopt a=20 policy of surveillance following surgery. The patient was closely = followed by=20 MRI every three months.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN> <B>a</B> = Axial=20 T1-weight MRI with gadolinium showed a nonenhancing lesion in the right=20 cerebellar peduncle. <B>b</B> Axial T2-weight MRI showed a = high-signal-intensity=20 lesion in the right cerebellar peduncle </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 2 </SPAN> <B>a</B> = H&E=20 staining shows an intermingled grade II oligoastrocytoma (400=D7). = <B>b</B>=20 Fluorescence in-situ hybridization to assess 19q status: a probe for = 19q13.4=20 (red in the online version of the figure) is paired with 10p13 (green in = the=20 online version of the figure); 19q is intact (fluorescent probe-stained = cells,=20 original magnification 1000=D7) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>In July, 2006 the patient was readmitted to the hospital with = symptoms of=20 dizziness, diplopia, and ataxia. MRI of the brain and spine showed = nodular=20 spread of the tumor in the brainstem, cerebellum, ventricles, and = leptomeninges.=20 The patient received whole brain radiotherapy (30 Gy for = 10 days), but=20 after two months an MRI showed further progression of the leptomeningeal = and=20 parenchymal dissemination with extensive enhancement in the cervical and = thoracic regions of the spinal cord (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig3">3</A>a=96d).=20 Analysis of the CSF showed mild hyperproteinorrhachia (1.17 g/L), = mild=20 hypoglycorrhachia, and the presence of malignant cells positive for = glial=20 fibrillary acid protein (GFAP).=20 <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig3_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig3_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 3 </SPAN> = <B>a</B>=96<B>d</B>=20 MRI showed progression of the leptomeningeal and parenchymal = dissemination with=20 extensive enhancement of cervical regions C4=96C5 and C6=96C7 and = thoracic region D2=20 </DIV> <HR> </DIV></DIV> <P>Because of the young age of the patient, good performance status = (Karnofsky=20 performance status >70), and tumor histology, a combination of = systemic and=20 intrathecal chemotherapy was started. In November, 2006 the patient = received=20 temozolomide at the standard dose of 200 mg/m<SUP>2</SUP> for five = days=20 every 28 days in combination with intralumbar liposomal cytarabine. = During=20 the induction phase, the patient received two doses of liposomal = cytarabine=20 50 mg every two weeks. The consolidation phase consisted of four = doses of=20 liposomal cytarabine 50 mg administered every two weeks, followed = by two=20 doses every four weeks. Maintenance therapy was administered once every = four=20 weeks for a total of six doses. Concomitant intravenous dexamethasone=20 (0.15 mg/kg) was given every 12 h from the day before = liposomal=20 cytarabine was infused until the fourth day after cytarabine treatment. = The=20 patient also received systemic chemotherapy with temozolomide for up to = 12=20 cycles. During treatment, neuroimaging studies for evaluation of disease = status=20 were performed every three months and as clinically indicated. In = addition, a=20 CSF examination was performed before each dose of liposomal cytarabine. = </P> <DIV class=3DPara> <DIV>MRI examination after three cycles of temozolomide and the = consolidation=20 phase of liposomal cytarabine revealed a reduction in subependymal = enhancing=20 lesions, but an increase in lesions in the cerebellar peduncles = (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig4">4</A>a=96d).=20 The patient had complete clearing of malignant cells from the CSF = following two=20 doses of liposomal cytarabine. At the end of the treatment = (12 months from=20 the start of treatment) the neurological status of the patient improved = and he=20 started to work. MRI showed the disappearance of lesions in both the = brain and=20 spinal cord (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig5">5</A>a=96d);=20 additionally, the CSF was negative for malignant cells. After a = follow-up of=20 24 months, the patient remained clinically stable and free from = relapse.=20 <DIV class=3DFigure><A name=3DFig4></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig4_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig4_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 4 </SPAN> = <B>a</B>=96<B>d</B>=20 MRI after three months of therapy showed a reduction of the subependymal = enhancing lesions, but an increase of the lesions in the cerebellar = peduncles=20 </DIV> <HR> <DIV class=3DFigure><A name=3DFig5></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig5_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig5_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 5 </SPAN> = <B>a</B>=96<B>d</B>=20 MRI after one year of the treatment showed a disappearance of the = lesions in=20 both the brain and spinal cord </DIV> <HR> </DIV></DIV> <P>Treatment was well tolerated, with no observed grade III/IV = hematologic or=20 non-hematologic toxicity. During treatment the patient developed a deep = vein=20 thrombosis of the right leg, which was treated with low-weight heparin, = and=20 partial seizures, which were controlled with valproic acid and = levetiracetam.=20 </P></DIV> <DIV><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P>Neoplastic meningitis is a serious and rare complication of LGG, with = a=20 median patient survival time ranging from a few weeks to a few months. = In=20 retrospective studies (some of which were published before the = introduction of=20 MRI), LMD was found in 5% of LGG patients at the time of diagnosis and = in 7=9610%=20 of patients at the time of tumor progression [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR3">3</A></CITE>].=20 Recent studies that included patient autopsies, however, have suggested = that the=20 incidence of LMD may be higher than previously reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR5">5</A></CITE>].=20 </P> <P>Current treatment of LMD is designed to improve or stabilize = neurological=20 symptoms and to prolong survival. Available treatment options include = focal=20 radiation therapy for bulky disease, intrathecal therapy, and systemic=20 chemotherapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR6">6</A></CITE>].=20 The failure of conventional therapy to improve survival or prevent = clinical=20 progression might be related to the difficulty in maintaining cytotoxic = levels=20 of chemotherapeutic agents in the cerebrospinal fluid (CSF) when using = standard=20 dosing and schedules. </P> <P>Recently, temozolomide, which is an oral alkylating agent with a = favorable=20 toxicity profile, has been shown to be active and particularly well = tolerated=20 when delivered as first-line therapy specifically to patients with = low-grade=20 gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR9">9</A></CITE>].=20 Objective response rates reported in the literature range from 31 to 66% = and the=20 median time to maximum response range from five to twenty months. = </P> <P>Few data are available on the pharmacokinetics of temozolomide in=20 cerebrospinal fluid (CSF). To the best of our knowledge Ostermann et al. = analyzed the pharmacokinetics of temozolomide in the plasma and = cerebrospinal=20 fluid of 35 patients with newly diagnosed or recurrent malignant gliomas = and=20 found that the temozolomide CSF penetration corresponds only to 20% of = systemic=20 TMZ exposure [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR10">10</A></CITE>].=20 </P> <P>Liposomal cytarabine is a slow-release formulation of cytarabine that = is=20 manufactured by encapsulating aqueous cytarabine in spherical = multivesicular=20 particles known as DepoFoam (DepoCyte; SkyePharma, San Diego, CA, USA) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR11">11</A></CITE>].=20 The pharmacokinetic advantage of this novel cytarabine formulation was=20 demonstrated in adult phase I studies in which the terminal half-life of = liposomal cytarabine was shown to be approximately 40 times longer than = that of=20 standard cytarabine [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR12">12</A></CITE>].=20 This liposomal form yielded cytotoxic levels of cytarabine in the CSF = for a=20 period of 14 days [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR13">13</A></CITE>].=20 Little has been published on the role of liposomal cytarabine in LMD = from=20 malignant glioma. Glantz et al. conducted a randomized, controlled trial = of=20 DepoCyte versus methotrexate (MTX) in 61 patients with neoplastic = meningitis=20 from histologically proven cancer and positive CSF cytologies. Responses = occurred in 26% of DepoCyte-treated and 20% of MTX-treated patients and = the=20 DepoCyte group experienced a greater median time to neurological = progression (58=20 versus 30 days), longer neoplastic meningitis-specific survival = (343 versus=20 98 days), and better quality of life in patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR14">14</A></CITE>].=20 These findings were confirmed also in the subgroup of patients=20 (<I>N</I> =3D 14) with LMD from malignant glioma. </P> <P>The patient described in our manuscript was young (43-year-old), had = a good=20 performance status (Karnofsky performance status >70), but was = strongly=20 symptomatic of the disease. On the basis of the previous prognostic = factors we=20 decided to offer to the patient an aggressive treatment to improve his=20 neurological status and prolong survival while maintaining a good = quality of=20 life. </P> <P>In our patient liposomal cytarabine combined with temozolomide was = both safe=20 and active.</P> <P>In the literature Lassaletta et al. published a case report of a = posterior=20 fossa ependymoma with leptomeningeal dissemination in a two-year-old = child,=20 successfully treated with a combination of systemic chemotherapy and = intrathecal=20 liposomal cytarabine [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P>To the best of our knowledge, there are no previous reports of the = use of=20 temozolomide in combination with liposomal cytarabine for treatment of=20 leptomeningeal spread from low-grade oligoastrocytomas. </P> <P>Although it is impossible to draw any conclusion about the = effectiveness of=20 these drugs in the treatment of LGG, we suggest that this combination = may be a=20 valuable treatment option for patients with LMD from low-grade glioma.=20 </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Grier JT, Batchelor T (2006) Low-grade gliomas = in=20 adults. 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From: Subject: 10.1007/s11060-009-0040-0 Date: Fri, 6 Nov 2009 10:31:07 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_04B6_01CA5ECC.4015F2C0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_04B6_01CA5ECC.4015F2C0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/h64x08156275rh71/fulltext.html 10.1007/s11060-009-0040-0</TIT= LE> <META content=3D"text/html; charset=3DISO-8859-1" = http-equiv=3DContent-Type><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/A++_common.css"><LINK=20 rel=3DstyleSheet type=3Dtext/css=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"> <META name=3DGENERATOR content=3D"MSHTML 8.00.6001.18852"></HEAD> <BODY class=3Dfor-print> <TABLE border=3D1 cellPadding=3D2> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0040-0</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Case Report</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Intrathecal liposomal = cytarabine in=20 combination with temozolomide in low-grade oligoastrocytoma with = leptomeningeal=20 dissemination </DIV> <P class=3DAuthorGroup>Maria Grazia Passarin<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#ContactOfAuthor1"><IMG=20 border=3D0 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/contact.gif">= </A></SUP>,=20 Giuseppe Moretto<SUP>2</SUP>, = Anna Maria Musso<SUP>2</SUP>,=20 Sarah Ottaviani<SUP>2</SUP>, Barbara Masotto<SUP>3</SUP>,=20 Claudio Ghimenton<SUP>4</SUP>, Paolo Iuzzolino<SUP>5</SUP>,=20 Ebba Buffone<SUP>1</SUP>, Roberta Rud=E0<SUP>6</SUP>,=20 Riccardo Soffietti<SUP>6</SUP>, Emanuela Vattemi<SUP>7</SUP> = and=20 Rebecca Pedersini<SUP>8</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neurology, USSL 22, Via = Ospedale=20 6, 37012 Bussolengo, Verona, = Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff2></A>(2) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neurology, Azienda=20 Ospedaliera-Universitaria di Verona, Verona,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff3></A>(3) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neurosurgery, Azienda=20 Ospedaliera-Universitaria di Verona, Verona,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff4></A>(4) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Pathology, Azienda=20 Ospedaliera-Universitaria di Verona, Verona,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff5></A>(5) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Pathology, Azienda = Ospedaliera di=20 Belluno, Belluno, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff6></A>(6) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Neuro-Oncology, University = of=20 Torino, Torino, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff7></A>(7) </SPAN></TD> <TD><SPAN class=3DAffiliation>Division of Medical Oncology, Central=20 Hospital, Bolzano, Italy</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff8></A>(8) </SPAN></TD> <TD><SPAN class=3DAffiliation>Spedali Civili, Brescia,=20 Italy</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG border=3D0 alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/contact.gif">= </TD> = <TD><STRONG>Maria </STRONG><STRONG>Grazia </STRONG><STRONG>Pass= arin</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:mariagraziapassarin@hotmail.it">mariagraziapassarin@hotmai= l.it</A></TD></TR></TBODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>3 August 2009 <STRONG>Accepted:=20 </STRONG>12 October 2009 <STRONG>Published online:=20 </STRONG>31 October 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>Leptomeningeal = dissemination of=20 low-grade gliomas is an uncommon event. A 43-year old male presented = with=20 dizziness, gait ataxia, and diplopia. A nonenhancing lesion in the right = cerebellar peduncle was identified, subtotally resected, and diagnosed = as a=20 grade II astrocytoma. After one year a nodular spread in the brain and=20 leptomeninges was diagnosed, so the patient started chemotherapy with=20 temozolomide and liposomal cytarabine. Complete remission was achieved = after=20 12 months of treatment and the patient is still free from the = disease after=20 a follow-up of 24 months. We suggest that this combination may be a = valuable treatment option. </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Leptomeningeal=20 carcinomatosis - Low-grade astrocytoma - Liposomal=20 cytarabine - Temozolomide </P> <DIV class=3DFulltext> <DIV><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P>Low-grade gliomas (LGG) are a group of relatively uncommon primary = brain=20 tumors, including astrocytomas, oligodendrogliomas, and mixed gliomas,=20 classified by the World Health Organization (WHO) grading system (2007) = as grade=20 2 lesions. The natural history of LGG shows great variability, and = optimum=20 disease management remains a challenge for the treating physician = [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR1">1</A></CITE>].=20 Leptomeningeal dissemination (LMD; also referred to as neoplastic = meningitis) is=20 a rare and serious complication of LGG. Current treatment of LMD is = designed to=20 improve or stabilize neurologic symptoms and to prolong survival. </P> <P>In this paper we report the case of a 43-year-old patient diagnosed = with LMD=20 from grade II oligoastrocytoma for whom complete remission was achieved = after=20 treatment with a sustained-release formulation of liposomal cytarabine = combined=20 with temozolomide. To the best of our knowledge, this is the first = report=20 describing long-lasting remission after treatment with this combination = in an=20 adult patient with LMD from low-grade oligoastrocytoma. </P></DIV> <DIV><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Case report</DIV> <DIV class=3DPara> <DIV>A 43-year-old male presented in July, 2005 with a five-month = history of=20 dizziness, gait ataxia, and intermittent diplopia. The patient had an=20 unremarkable medical history and no relevant family history of disease. = Magnetic=20 resonance imaging (MRI) revealed a nonenhancing lesion in the right = cerebellar=20 peduncle (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig1">1</A>).=20 The patient underwent surgery and partial resection of the tumor was = performed.=20 Histologic examination revealed a grade II astrocytoma (WHO) with an=20 oligodendroglial component (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig2">2</A>a),=20 and no 1p/19q co-deletion (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig2">2</A>b).=20 After surgery, the symptoms improved, therefore we considered it safe to = adopt a=20 policy of surveillance following surgery. The patient was closely = followed by=20 MRI every three months.=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 1 </SPAN> <B>a</B> = Axial=20 T1-weight MRI with gadolinium showed a nonenhancing lesion in the right=20 cerebellar peduncle. <B>b</B> Axial T2-weight MRI showed a = high-signal-intensity=20 lesion in the right cerebellar peduncle </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig2_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig2_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 2 </SPAN> <B>a</B> = H&E=20 staining shows an intermingled grade II oligoastrocytoma (400=D7). = <B>b</B>=20 Fluorescence in-situ hybridization to assess 19q status: a probe for = 19q13.4=20 (red in the online version of the figure) is paired with 10p13 (green in = the=20 online version of the figure); 19q is intact (fluorescent probe-stained = cells,=20 original magnification 1000=D7) </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV>In July, 2006 the patient was readmitted to the hospital with = symptoms of=20 dizziness, diplopia, and ataxia. MRI of the brain and spine showed = nodular=20 spread of the tumor in the brainstem, cerebellum, ventricles, and = leptomeninges.=20 The patient received whole brain radiotherapy (30 Gy for = 10 days), but=20 after two months an MRI showed further progression of the leptomeningeal = and=20 parenchymal dissemination with extensive enhancement in the cervical and = thoracic regions of the spinal cord (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig3">3</A>a=96d).=20 Analysis of the CSF showed mild hyperproteinorrhachia (1.17 g/L), = mild=20 hypoglycorrhachia, and the presence of malignant cells positive for = glial=20 fibrillary acid protein (GFAP).=20 <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig3_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig3_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 3 </SPAN> = <B>a</B>=96<B>d</B>=20 MRI showed progression of the leptomeningeal and parenchymal = dissemination with=20 extensive enhancement of cervical regions C4=96C5 and C6=96C7 and = thoracic region D2=20 </DIV> <HR> </DIV></DIV> <P>Because of the young age of the patient, good performance status = (Karnofsky=20 performance status >70), and tumor histology, a combination of = systemic and=20 intrathecal chemotherapy was started. In November, 2006 the patient = received=20 temozolomide at the standard dose of 200 mg/m<SUP>2</SUP> for five = days=20 every 28 days in combination with intralumbar liposomal cytarabine. = During=20 the induction phase, the patient received two doses of liposomal = cytarabine=20 50 mg every two weeks. The consolidation phase consisted of four = doses of=20 liposomal cytarabine 50 mg administered every two weeks, followed = by two=20 doses every four weeks. Maintenance therapy was administered once every = four=20 weeks for a total of six doses. Concomitant intravenous dexamethasone=20 (0.15 mg/kg) was given every 12 h from the day before = liposomal=20 cytarabine was infused until the fourth day after cytarabine treatment. = The=20 patient also received systemic chemotherapy with temozolomide for up to = 12=20 cycles. During treatment, neuroimaging studies for evaluation of disease = status=20 were performed every three months and as clinically indicated. In = addition, a=20 CSF examination was performed before each dose of liposomal cytarabine. = </P> <DIV class=3DPara> <DIV>MRI examination after three cycles of temozolomide and the = consolidation=20 phase of liposomal cytarabine revealed a reduction in subependymal = enhancing=20 lesions, but an increase in lesions in the cerebellar peduncles = (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig4">4</A>a=96d).=20 The patient had complete clearing of malignant cells from the CSF = following two=20 doses of liposomal cytarabine. At the end of the treatment = (12 months from=20 the start of treatment) the neurological status of the patient improved = and he=20 started to work. MRI showed the disappearance of lesions in both the = brain and=20 spinal cord (Fig. <A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#Fig5">5</A>a=96d);=20 additionally, the CSF was negative for malignant cells. After a = follow-up of=20 24 months, the patient remained clinically stable and free from = relapse.=20 <DIV class=3DFigure><A name=3DFig4></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig4_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig4_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 4 </SPAN> = <B>a</B>=96<B>d</B>=20 MRI after three months of therapy showed a reduction of the subependymal = enhancing lesions, but an increase of the lesions in the cerebellar = peduncles=20 </DIV> <HR> <DIV class=3DFigure><A name=3DFig5></A><IMG=20 alt=3DMediaObjects/11060_2009_40_Fig5_HTML.jpg=20 src=3D"http://www.springerlink.com/content/h64x08156275rh71/MediaObjects/= 11060_2009_40_Fig5_HTML.jpg"></DIV> <DIV class=3DCapt><SPAN class=3DCaptNr>Fig. 5 </SPAN> = <B>a</B>=96<B>d</B>=20 MRI after one year of the treatment showed a disappearance of the = lesions in=20 both the brain and spinal cord </DIV> <HR> </DIV></DIV> <P>Treatment was well tolerated, with no observed grade III/IV = hematologic or=20 non-hematologic toxicity. During treatment the patient developed a deep = vein=20 thrombosis of the right leg, which was treated with low-weight heparin, = and=20 partial seizures, which were controlled with valproic acid and = levetiracetam.=20 </P></DIV> <DIV><A name=3DSec3></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P>Neoplastic meningitis is a serious and rare complication of LGG, with = a=20 median patient survival time ranging from a few weeks to a few months. = In=20 retrospective studies (some of which were published before the = introduction of=20 MRI), LMD was found in 5% of LGG patients at the time of diagnosis and = in 7=9610%=20 of patients at the time of tumor progression [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR3">3</A></CITE>].=20 Recent studies that included patient autopsies, however, have suggested = that the=20 incidence of LMD may be higher than previously reported [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR5">5</A></CITE>].=20 </P> <P>Current treatment of LMD is designed to improve or stabilize = neurological=20 symptoms and to prolong survival. Available treatment options include = focal=20 radiation therapy for bulky disease, intrathecal therapy, and systemic=20 chemotherapy [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR6">6</A></CITE>].=20 The failure of conventional therapy to improve survival or prevent = clinical=20 progression might be related to the difficulty in maintaining cytotoxic = levels=20 of chemotherapeutic agents in the cerebrospinal fluid (CSF) when using = standard=20 dosing and schedules. </P> <P>Recently, temozolomide, which is an oral alkylating agent with a = favorable=20 toxicity profile, has been shown to be active and particularly well = tolerated=20 when delivered as first-line therapy specifically to patients with = low-grade=20 gliomas [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR7">7</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR9">9</A></CITE>].=20 Objective response rates reported in the literature range from 31 to 66% = and the=20 median time to maximum response range from five to twenty months. = </P> <P>Few data are available on the pharmacokinetics of temozolomide in=20 cerebrospinal fluid (CSF). To the best of our knowledge Ostermann et al. = analyzed the pharmacokinetics of temozolomide in the plasma and = cerebrospinal=20 fluid of 35 patients with newly diagnosed or recurrent malignant gliomas = and=20 found that the temozolomide CSF penetration corresponds only to 20% of = systemic=20 TMZ exposure [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR10">10</A></CITE>].=20 </P> <P>Liposomal cytarabine is a slow-release formulation of cytarabine that = is=20 manufactured by encapsulating aqueous cytarabine in spherical = multivesicular=20 particles known as DepoFoam (DepoCyte; SkyePharma, San Diego, CA, USA) = [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR11">11</A></CITE>].=20 The pharmacokinetic advantage of this novel cytarabine formulation was=20 demonstrated in adult phase I studies in which the terminal half-life of = liposomal cytarabine was shown to be approximately 40 times longer than = that of=20 standard cytarabine [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR12">12</A></CITE>].=20 This liposomal form yielded cytotoxic levels of cytarabine in the CSF = for a=20 period of 14 days [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR13">13</A></CITE>].=20 Little has been published on the role of liposomal cytarabine in LMD = from=20 malignant glioma. Glantz et al. conducted a randomized, controlled trial = of=20 DepoCyte versus methotrexate (MTX) in 61 patients with neoplastic = meningitis=20 from histologically proven cancer and positive CSF cytologies. Responses = occurred in 26% of DepoCyte-treated and 20% of MTX-treated patients and = the=20 DepoCyte group experienced a greater median time to neurological = progression (58=20 versus 30 days), longer neoplastic meningitis-specific survival = (343 versus=20 98 days), and better quality of life in patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR14">14</A></CITE>].=20 These findings were confirmed also in the subgroup of patients=20 (<I>N</I> =3D 14) with LMD from malignant glioma. </P> <P>The patient described in our manuscript was young (43-year-old), had = a good=20 performance status (Karnofsky performance status >70), but was = strongly=20 symptomatic of the disease. On the basis of the previous prognostic = factors we=20 decided to offer to the patient an aggressive treatment to improve his=20 neurological status and prolong survival while maintaining a good = quality of=20 life. </P> <P>In our patient liposomal cytarabine combined with temozolomide was = both safe=20 and active.</P> <P>In the literature Lassaletta et al. published a case report of a = posterior=20 fossa ependymoma with leptomeningeal dissemination in a two-year-old = child,=20 successfully treated with a combination of systemic chemotherapy and = intrathecal=20 liposomal cytarabine [<CITE><A=20 href=3D"http://www.springerlink.com/content/h64x08156275rh71/fulltext.htm= l#CR15">15</A></CITE>].=20 </P> <P>To the best of our knowledge, there are no previous reports of the = use of=20 temozolomide in combination with liposomal cytarabine for treatment of=20 leptomeningeal spread from low-grade oligoastrocytomas. </P> <P>Although it is impossible to draw any conclusion about the = effectiveness of=20 these drugs in the treatment of LGG, we suggest that this combination = may be a=20 valuable treatment option for patients with LMD from low-grade glioma.=20 </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Grier JT, Batchelor T (2006) Low-grade gliomas = in=20 adults. 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Arch Neurol 52:912=96917<BR><A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ASTN%3A280%3= ADyaK2MzptVygtw%253D%253D&md5=3Dab48d852f08b51af7ef9f4dc5ffb5ab0"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D7661730"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> </TD></TR> <TR vAlign=3Dtop> <TD>13.</TD> <TD><A name=3DCR13></A>Jaeckle KA, Batchelor T, O=92Day SJ, = Phuphanich S, New=20 P, Lesser G et al (2002) An open label trial of sustained-release=20 cytarabine (DepoCyt) for the intrathecal treatment of solid tumor=20 neoplastic meningitis. 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two-year-old child.=20 J Neurooncol 83(3):303=96306<BR><A=20 href=3D"http://dx.doi.org/10.1007/s11060-006-9327-6" = target=3D_blank><IMG=20 border=3D0 alt=3DSpringerLink=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/springer_link= .gif"=20 width=3D108 height=3D20></A> <A=20 = href=3D"http://chemport.cas.org/cgi-bin/sdcgi?APP=3Dftslink&action=3D= reflink&origin=3Dspringer&version=3D1.0&coi=3D1%3ACAS%3A528%3= ADC%252BD2sXosVarurk%253D&md5=3D6eef4c7063e60611a5097ab19eb68840"=20 target=3D_blank><IMG border=3D0 alt=3DChemPort=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/chemport_link= .gif"=20 width=3D65 height=3D20></A> <A=20 = href=3D"http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=3DRetrieve&= db=3DPubMed&dopt=3DAbstract&list_uids=3D17245619"=20 target=3D_blank><IMG border=3D0 alt=3DPubMed=20 = src=3D"http://www.springerlink.com/content/h64x08156275rh71/pubmed_link.g= if"=20 width=3D65 height=3D20></A> </TD></TR> <TR> <TD> 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