10.1007/s11060-010-0136-6</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.17023" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2010</TD></TR> <TR> <TD>10.1007/s11060-010-0136-6</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>A lower-dose, lower-toxicity=20 cisplatin=96etoposide regimen for childhood progressive low-grade glioma = </DIV> Maura Massimino1 <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/contact.gif" = border=3D0></A>, Filippo Spreafico1,=20 Daria Riva5, Veronica Biassoni1,=20 Geraldina Poggi7, Carlo Solero6,=20 Lorenza Gandola2, Lorenzo Genitori8,=20 Piergiorgio Modena4, Fabio Simonetti1,=20 Paolo Potepan3, Michela Casanova1,=20 Cristina Meazza1, = Carlo A. Clerici1,=20 Serena Catania1, Iacopo Sardi8 and=20 Felice Giangaspero9 <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff1></A>(1) </TD> <TD>Division of Paediatrics, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff2></A>(2) </TD> <TD>Division of Radiotherapy, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff3></A>(3) </TD> <TD>Division of Radiology, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff4></A>(4) </TD> <TD>Molecular Biology Unit, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff5></A>(5) </TD> <TD>Department of Developmental Neurology, = Fond.=20 IRCCS Istituto Neurologico C. Besta, Via Celoria, = 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff6></A>(6) </TD> <TD>Neurosurgery Unit, Fond. IRCCS = Istituto=20 Neurologico C. Besta, Via Celoria, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff7></A>(7) </TD> <TD>Acquired Lesions Division Unit, = Istituto=20 Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, = Lecco,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff8></A>(8) </TD> <TD>Neurosurgery Unit, Osp. Meyer, Viale=20 Pieraccini, 24-50139 Florence, = Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff9></A>(9) </TD> <TD>Neuropathology (FG) Unit, University = La=20 Sapienza 00151 Roma and Neuromed, Via Atinense, = 18-86077 Pozzilli,=20 IS, Italy</TD></TR></TBODY></TABLE> <A name=3DContactOfAuthor1></A> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/c34647v88t66m727/contact.gif" = border=3D0></TD> = <TD>Maura Massimino</STRON= G> Email:=20 <A=20 = href=3D"mailto:maura.massimino@istitutotumori.mi.it">maura.massimino@isti= tutotumori.mi.it</A></TD></TR></TBODY></TABLE> Received:=20 23 November 2009 Accepted:=20 25 January 2010 Published online:=20 12 February 2010 <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract After successfully = using=20 cisplatin (30 mg/m2/day) and etoposide=20 (150 mg/m2/day) in ten three-day courses for progressive = low-grade gliomas, a subsequent protocol reduced the daily doses of = cisplatin=20 (to 25 mg) and etoposide (to 100 mg), with the objective of = achieving=20 the same response and three-year PFS rates with lower neurotoxicity and=20 myelotoxicity. We treated 37 patients (median age 6 years); 23 had=20 optochiasmatic tumours and nine were metastatic cases. Diagnoses were = clinical=20 in 13 cases and histological in 24, and comprised: pilocytic astrocytoma = (17),=20 ganglioglioma (3), pilomyxoid astrocytoma (2), and fibrillary = astrocytoma (2).=20 Treatment was prompted by radiological evidence of progression and/or = clinical=20 deterioration a median 18 months after the first diagnosis. After = initial=20 MRI staging, neurological and clinical examinations were performed = before each=20 chemotherapy cycle, with MRI after the first three courses and every = three=20 months thereafter. After a median 48 months, a volume reduction was = appreciable in 24 cases (65%) and response was maximum 12 months = after=20 starting treatment. The three-year EFS and OS rates were 65 and 97%,=20 respectively. Clinical, neurological, or functional improvements were = seen in=20 26/37 cases. No children had a WBC nadir below 2,000/mm3.=20 Audiological toxicity caused damage in 4/34 cases. The previous protocol = had=20 achieved volume reductions in 70% of cases, causing audiological damage = (data=20 updated) in 11/31 (P =3D 0.023), with three-year PFS = and OS rates=20 of 70 and 100%, respectively. Lower doses of cisplatin/etoposide are = still=20 effective in progressive low-grade glioma, with less acute and = persistent=20 morbidity. </DIV> Keywords Childhood=20 low-grade glioma - Chemotherapy for brain=20 tumours - Ototoxicity - Tumour = response - Symptom=20 amelioration <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> For 20 years chemotherapy has been used in children = with=20 inoperable progressive low-grade glioma (LGG) or large symptomatic = tumours with=20 a view to delaying radiotherapy, especially in younger patients with = large=20 tumours or diencephalic syndrome [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR1">1</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR3">3</A></CITE>].=20 Many schedules have been described, mainly including carboplatin, = vincristine,=20 etoposide, nitroso ureas, cisplatin, actinomycin-D, cyclophosphamide,=20 procarbazine, 6-thioguanine [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR1">1</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR4">4</A></CITE>],=20 and, more recently, vinblastine [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR5">5</A></CITE>]=20 and imatinib [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR6">6</A></CITE>].=20 Having obtained satisfactory results with a regimen of = cisplatin=20 (30 mg/m2/day) and etoposide = (150 mg/m2/day) in=20 ten three-day courses [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR7">7</A></CITE>],=20 we launched a new institutional protocol with lower daily doses of both = drugs.=20 The design of the protocol was a non-inferiority study = whose=20 primary objectives were to maintain the same rates of response and = three-year=20 progression-free survival with lower neurotoxicity (based on audiograms = or other=20 age-tailored acoustic tests) and myelotoxicity. We report the results = obtained=20 in this new series of patients. </DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Eligibility</DIV> All children under 18 years of age with radiological = or=20 symptomatic evidence of inoperable progressive low-grade glioma were = eligible=20 for treatment irrespective of their age or the tumour=92s origin and=20 dissemination. Histology of low-grade glioma classified according to WHO = was=20 required except in cases of optochiasmatic tumours in NF1, or when = surgery was=20 considered dangerous and the clinical and radiological signs clearly = pointed to=20 a low-grade glioma. Previous chemotherapy treatment, apart from = steroids, was=20 not allowed. </DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Chemotherapy schedule</DIV> Cisplatin was given as a 2-h infusion at=20 25 mg/m2/day on days 1=963, followed by etoposide = infused in=20 30 min at a dose of 100 mg/m2/day, again on days = 1=963; the=20 drugs were preceded and followed by a 2-h hydration. In children under = one year=20 old or weighing less than 10 kg, the doses were adjusted to their = weight.=20 The interval between cycles lasted four weeks for the first four cycles, = five=20 weeks for the next three cycles, and six weeks for the last three, = aiming to=20 cover a period of approximately 10=9611 months with 10 cycles in = all, giving=20 total doses of 750 mg/m2 cisplatin and=20 3,000 mg/m2 etoposide. The protocol was approved by our institution=92s ethical = and=20 scientific committee, and formal consent was obtained from the = patients=92=20 parents. The therapy was always administered on an outpatient = basis, except=20 for the first course, which was given during a hospital stay if the = patient was=20 fitted with a central venous catheter. </DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Evaluation of response</DIV> Initial staging included magnetic resonance imaging (MRI) = of the=20 brain and spine in all patients. When multiple sites of disease emerged = at MRI,=20 cytology of the spinal fluid was performed. Follow-up during the = treatment was=20 based on neurological and clinical assessments before each chemotherapy = cycle,=20 plus MRI of the tumour site after the first three cycles, then every = three=20 months thereafter for the first year. Tumour volume was calculated from=20 T2-weighted and enhanced T1-weighted MRI scans. Thorough neurological = and=20 clinical assessments were repeated every four months for the first three = years=20 after completing the treatment, then every six months up to the fifth = year, then=20 yearly. In the event of neurofunctional impairment, specific tests = (visual field=20 and acuity, visual-evoked potentials (VEP)) were prescribed at the same = time as=20 the radiological evaluation. Visual field assessments and visual-evoked=20 potentials were obtained at six-month intervals, wherever feasible, with = audiometric evaluation (vocal, behavioural audiometry, auditory = brainstem=20 responses or acoustic oto-emission testing, depending on the patient=92s = age)=20 during the first five years after the glioma was diagnosed. = Endocrinological=20 tests were also performed routinely and repeated if a patient showed = clinical=20 signs of any endocrinological changes. Radiological response was = assessed=20 according to International Society of Paediatric Oncology criteria and=20 protocols, i.e. complete response was defined as no evidence of disease, = partial=20 response meant a more than 50% radiographically evident size reduction, = and=20 stable disease meant no signs of tumour progression. We also considered=20 objective response, i.e. a 25=9650% size reduction in unequivocal = residual tumour=20 (the product of the two largest perpendicular diameters) [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR8">8</A></CITE>].=20 All MRI were reviewed by one of the authors (PP). All patients were = still being=20 actively followed up at the time of this report. </DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Toxicity evaluation</DIV> Audiotoxicity was monitored in all patients during the = treatment=20 using full-tone audiometry, acoustic potentials, or acoustic = oto-emission=20 testing (depending on their age) and then as explained in the previous = paragraph=20 after the treatment ended. When full-tone audiometry was feasible, the = rules for=20 stopping the treatment because of toxicity were those commonly adopted = for=20 medulloblastoma treated with a regimen containing platinum; audiometry = was=20 performed before every treatment course in children with NF1 and after = two or=20 three courses in the others. In the case of a loss of perception beyond=20 40 dB at 4,000=968,000 Hz, the cisplatin was to be replaced = with=20 carboplatin at a dose of 400 mg/m2 on the first day of = the next=20 course. In the absence of standard criteria for stopping chemotherapy in = the=20 light of other ototoxicity tests, all other patients were assessed case = by case.=20 </DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Statistical analysis</DIV> Life tables were obtained for all patients. Overall and = event-free=20 survival rates were calculated according to the Kaplan=96Meier method = [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR9">9</A></CITE>].=20 Class comparisons were drawn using the log-rank test. </DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Results</DIV> Patient accrual lasted from November 2001 to December = 2007; 22 males=20 and 15 females were enrolled; the median age was 72 months (range=20 6=96198 months) at the time of their treatment. Median follow-up at = the time=20 of writing of this report was 48 months. <DIV class=3DPara> <DIV class=3D"">The main demographic features of this series are given = in=20 Table <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Tab1">1</A>.<A=20 name=3DTab1></A> <DIV class=3DCapt>Table 1 Main=20 demographic features of the series </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> Patient</TH> <TH align=3Dleft> Sex</TH> <TH align=3Dleft char=3D"."> Age</TH> <TH align=3Dleft> Histology</TH> <TH align=3Dleft> NF1</TH> <TH align=3Dleft> Site</TH> <TH align=3Dleft> Meta</TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> 1</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 2</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Multi-nodular</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 3</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 10.08</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 4</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 3.09</TD> <TD align=3Dleft> Fibrillary</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 5</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 1.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 6</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 9.03</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 7</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.07</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 8</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 0.07</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 9</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> Fibrillary</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 10</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 13.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 11</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 12</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 0.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 13</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 14.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Temporal</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 14</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 0.05</TD> <TD align=3Dleft> Pilomixoid</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 15</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 12.00</TD> <TD align=3Dleft> Ganglioglioma</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 16</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 2.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 17</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 0.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 18</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 19</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 11.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 20</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 2.00</TD> <TD align=3Dleft> Ganglioglioma</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Multi-nodular</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 21</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 22</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 23</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 1.10</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 24</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 25</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 12.06</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 26</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.10</TD> <TD align=3Dleft> Ganglioglioma</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 27</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 6.05</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 28</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 29</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 13.02</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 30</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 2.06</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 31</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 32</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 33</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 1.04</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Pan-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 34</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 7.10</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 35</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 4.02</TD> <TD align=3Dleft> Pilomixoid</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 36</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 1.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 37</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 4.01</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D"">y, yes; n, no</DIV></DIV></DIV></DIV></DIV> When chemotherapy was begun, all the children were = suffering from=20 radiologically evident progressive disease and/or worsening symptoms; = the median=20 time from the tumour=92s diagnosis to the start of the treatment was=20 18 months (range 1 month=9610 years). Seven children had=20 neurofibromatosis type 1 (NF1) and one other child had an unknown = neurocutaneous=20 syndrome with cervico-medullary glioma, spinal and subcutaneous lipomas = and=20 mental retardation; all the other patients had sporadic tumours. <DIV class=3DPara> <DIV class=3D"">The tumour originated in the = optochiasmatic=96diencephalic region in=20 23 cases: 22 children had a Dodge 3 extension and one had a Dodge 1 = tumour. Five=20 children had tumours in the cervico=96medullary region, five gliomas = were=20 mesencephalo=96thalamic, two were multinodular with no clear primary = site, one=20 glioma occupied the whole spine, and one was temporal. In all, nine = children=20 presented with nodular metastases and one had a diagnosis of NF1. All = patients=20 with metastases had secondary nodules evident first in the brain, and=20 subsequently confirmed by MRI in the spine, except for one girl who had = sciatic=20 nerve pain prompting spinal MRI (Fig. <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig1">1</A>).=20 Liquoral seeding was never documented by cephalo=96spinal cytology. = Twenty-four=20 children underwent surgery (partial tumour resections in 18 cases and = biopsies=20 in six), enabling a histological diagnosis in all cases. The centrally = reviewed=20 (FG) histological diagnoses were: pilocytic astrocytoma in 17 cases, = pilomyxoid=20 astrocytoma in two, ganglioglioma in three, and fibrillary astrocytoma = in two.=20 The diagnoses were concordant in 22/24 cases, and two tumours previously = diagnosed as grade 3 astrocytoma were downgraded to pilocytic = astrocytoma. The=20 other 13 children were diagnosed on clinical grounds alone: 12 had=20 optochiasmatic tumours and one was a 23-month-old child with a = cervico=96medullary=20 tumour who had a recent history of rapid loss of limb strength and gait=20 competence and was sent urgently for primary adjuvant treatment after a=20 multidisciplinary discussion concluded that a low-grade glioma was = highly=20 likely. The signs and symptoms prompting these diagnoses were eyesight=20 deficiencies in 23 cases, pyramidal deficiencies in 15, diencephalic = syndrome in=20 four, cranial nerve palsy in two, monolateral proptosis in one and = intractable=20 seizures in one. Other functional alterations were early puberty in = three cases=20 and panhypopituitarism in three, obesity in one, and isolated growth = hormone=20 deficiency in one; one child developed diabetes insipidus after surgery. = <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2010_136_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/MediaObjects/= 11060_2010_136_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt>Fig. 1 Chiasmatic/metastatic=20 tumour </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV class=3D"">After chemotherapy, radiology revealed tumour reductions = in 24/37=20 cases, meeting the criteria for partial remission in 17 of these and of = complete=20 remission in one. To date, the maximum response was recorded a median=20 12 months (range 2=9631 months) after starting the treatment.=20 Table <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Tab2">2</A>=20 shows how the main signs and symptoms evolved during and after the = treatment. As=20 for sight impairments, 17/23 children with optochiasmatic tumours could = be=20 assessed adequately with consistent tests at the start and end of the=20 chemotherapy, as explained above: seven improved and the other ten were = stable;=20 of the six remaining patients, three could only undergo behavioural = sight=20 evaluation at the beginning of their course of chemotherapy, and were = judged to=20 have improved during and after treatment, whereas two were blind after = surgery=20 and one only underwent an instrumental assessment at the end of the = treatment=20 because of non-compliance.<A name=3DTab2></A> <DIV class=3DCapt>Table 2 Main = signs and=20 symptoms evolving during and after treatment </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Sight deficits 23</TD> <TD align=3Dleft> Improvement 7, stable others</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Diencephalic syndrome 4</TD> <TD align=3Dleft> Improvement 4</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Proptosis 1</TD> <TD align=3Dleft> Improvement 1</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Pyramidal deficits 15</TD> <TD align=3Dleft> Improvement 12 Stable 1 Worse 2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Cran.nerves palsy 2</TD> <TD align=3Dleft> Improvement 2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Seizures 1</TD> <TD align=3Dleft> Improvement 1</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> As a total, of 37</TD> <TD align=3Dleft> Improvement 26 Stable 9 Worse 2</TD></TR></TBODY></TABLE></DIV></DIV> <DIV class=3DPara> <DIV class=3D"">Three-year progression-free survival (PFS) and overall = survival=20 (OS) were 65.5 =B1 8.5 and 97 =B1 3%, respectively, = for all=20 patients (Fig. <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig2">2</A>);=20 five-year PFS and OS were 60 =B1 9.6 and = 86.4 =B1 8%,=20 respectively. For the purposes of this report, we updated the follow-up = on all=20 28 patients in our first reported series who had not been pre-treated, = whose=20 median follow-up was 113 months: their three-year PFS was = 86 =B1 7%=20 and their OS 96 =B1 3.5% (P ns); their five-year PFS = and OS were=20 74.5 =B1 8.3 and 96 =B1 3.5%, respectively. If we = compare only=20 the patients without metastatic deposits in the two series, the = three-year PFS=20 rates are 85 =B1 7% for the first series and = 75 =B1 9% for the=20 second (P ns), and the three-year OS are 96.3 =B1 4 and = 96.3 =B1 3%.=20 <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2010_136_Fig2_HTML.gif=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/MediaObjects/= 11060_2010_136_Fig2_HTML.gif"></DIV> <DIV class=3DCapt>Fig. 2 Fig <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig1">1</A>=20 PFS and OS for the whole series </DIV> <HR> </DIV></DIV> So far, 13 children have had adverse events, occurring a = median=20 26 months after starting the treatment. Tumours progressed in 12 = children=20 and one (the child with mental retardation and an unidentified = neurocutaneous=20 syndrome) died of ab ingestis pneumonia while on the treatment. = Another=20 four children died 39, 49, 61, and 62 months after starting the = treatment,=20 two because of tumour bleeding after re-surgery, one of a glioblastoma=20 developing 44 months after irradiation for fibrillary astrocytoma=20 progression, and one while on radiotherapy for rapid tumour progression; = one=20 other child developed a glioblastoma 14 months after radiotherapy = for a=20 progressive fibrillary astrocytoma. Tumour progression was local in nine = patients and in metastatic nodules in three, all of whom had already = presented=20 with metastases at the time of their diagnosis. Radiation-free survival for the 32 surviving children was=20 94 =B1 4.3% at both three and five years. <DIV class=3DPara> <DIV class=3D"">Children with metastatic disease had a significantly = lower=20 three-year PFS, i.e. 39 =B1 17% as opposed to = 75 =B1 9% in those=20 without metastases (P =3D 0.0149; Fig. <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig3">3</A>).=20 <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2010_136_Fig3_HTML.gif=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/MediaObjects/= 11060_2010_136_Fig3_HTML.gif"></DIV> <DIV class=3DCapt>Fig. 3 PFS for = cases=20 with/without metastases </DIV> <HR> </DIV></DIV> In univariate analysis, age under 12 months or over = five years,=20 NF1, gender, tumour originating in the optochiasmatic region, and = debulking=20 surgery as opposed to biopsy had no statistical effect on PFS or OS. It = is worth=20 emphasizing, however, that only one of the seven children with NF1 has = relapsed=20 so far and this child had ubiquitous tumour deposits at diagnosis. On = pooling=20 our first and second series, the three-year PFS for 15 children with NF1 = was=20 93 =B1 6% and their OS was 100%. <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Toxicity</DIV> The leukocyte nadir was always above = 2.0 =D7 109/l after the=20 first course of treatment and was, consequently, not checked again = between=20 courses. No infections were documented. None of the children had to stop = the=20 treatment because of toxicity. Audiological toxicity was evaluated according to the Brock = grading=20 system [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR10">10</A></CITE>]=20 after completing all the planned treatment in 34 children: grade 1 = audiological=20 damage was documented in one child, grade 0 in two, and acoustic = potential=20 deficiencies in one. For both the patients graded as 0, this meant a = 20 dB=20 loss at 4,000 Hz. In our first series, damage had been recorded in = 11/31=20 cases, classified as grade 1 in six, grade 2 in three and grade 0 in two = (P =3D 0.023); the toxicity in the two patients graded = as 0 meant=20 a 20 dB loss at 8,000 Hz in both cases. All patients were assessed by a psychiatrist at diagnosis = and=20 tailored rehabilitation was provided, as appropriate. Endocrine tests = were=20 included in the diagnostic work-up and in the subsequent follow-up.=20 </DIV></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Discussion</DIV> In previous reports on the efficacy of chemotherapy in = preventing=20 the progression or inducing the regression of paediatric low-grade = gliomas, many=20 authors describe institutional, national, or international trials using=20 different drug combinations given to cases inoperable because of the = site,=20 diffusion, or the clinical aggressiveness of the disease (i.e. rapid = recurrence=20 after surgery), or when radiotherapy was considered too harmful in view = of the=20 tumour=92s extent and the patient=92s young age [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR1">1</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR4">4</A></CITE>].=20 Given that most children presenting with the = above-described=20 features have tumours arising in visual pathways, causing more or less = severe=20 eyesight deficiencies, we were concerned to find that, although good = results=20 were achieved in terms of tumour response and PFS in our first reported = series=20 treated with cisplatin and etoposide, 28% of these children developed = hearing=20 impairments [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR7">7</A></CITE>].=20 Another issue was the potentially cumulative toxicity of etoposide, = especially=20 in patients with neurofibromatosis. Hence this second trial using substantially reduced doses = of=20 cisplatin (17% less) and etoposide (34% less). We recorded much the same results, in terms of three-year = PFS and=20 OS, as in the earlier series of patients: the tumour (evaluated using = the same=20 criteria in the two series) shrank in 20/28 patients in the first series = and in=20 24/37 in the second, confirming a very similar response. The time to = maximum=20 response differed substantially between the two series, however, being a = median=20 8 months for the first and 12 months for the second, prompting = us to=20 suggest that cumulative quantities of cisplatin (around=20 700=96750 mg/m2) and etoposide (around=20 3,000=963,600 mg/m2) are needed to obtain the maximum = response=20 with this regimen. We also deduce that higher cumulative doses are = responsible=20 for greater toxicity, but fail to improve or extend tumour response. = Unlike our=20 earlier series [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR7">7</A></CITE>],=20 no prognostic significance emerged from our second series for patients = below one=20 year old or over five years old. A possible explanation of this = discrepancy=20 might lie in the different numbers after subgroup stratification, i.e. = there=20 were more over five-year-olds and fewer under one-year-olds in our = second=20 series. It is also worth mentioning that our second series = included an=20 unusually large proportion of patients with metastases=97over 24% of all = the=20 consecutively treated children=97whereas the rates reported in the = literature are=20 under 10%, even in these modern times of MRI [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR12">12</A></CITE>].=20 The PFS rate was significantly lower for the subgroup of metastatic = patients,=20 despite 7/9 of them responding to the treatment. This emphasizes the = need to=20 find a different approach, possibly including other drugs, if genetics = succeed=20 in revealing a particular profile for tumours with this pattern of = presentation,=20 as recently demonstrated for pilocytic astrocytoma originating at other = sites=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR13">13</A></CITE>].=20 In our experience, the two children with fibrillary = astrocytoma=20 fared very badly, their tumour evolving into glioblastoma. According to = the=20 recent literature, grade 1 and grade 2 astrocytoma are clearly = distinguishable=20 at the molecular level in children [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR15">15</A></CITE>]=20 and in adults, so a tumour=92s evolution from fibrillary astrocytoma to=20 glioblastoma may be related to radiotherapy or it may be spontaneous, as = is more=20 often the case in adults [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR16">16</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR18">18</A></CITE>].=20 In our two fibrillary astrocytoma cases the IDH1 mutation, that = correlates with=20 adult low-grade glioma evolution into glioblastoma, was not found. The rapid disease progression and death of a third patient = with a=20 pilocytic astrocytoma of the visual pathway (presenting with huge = metastases=20 already at diagnosis) was rather unexpected, although there are reports = of=20 similar evolution in the literature and the recent histopathological=20 stratification of pilocytic astrocytoma can clarify such cases with a=20 particularly poor outcome [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR19">19</A></CITE>].=20 In addition to the radiological response, we also = considered the=20 signs and symptoms prompting our patients=92 diagnosis, which improved = in 70% of=20 cases. As Gutmann also pointed out, given the slow growth rate and = infiltrative=20 nature of low-grade glioma in children, a reduction in overall tumour = volume=20 cannot be the only endpoint of clinical trials on these diseases = [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR20">20</A></CITE>].=20 Changes in clinical variables may be very difficult to assess [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR4">4</A></CITE>]=20 because, for example, of the lack of standardized methods of = ophthalmological=20 evaluation, the patients=92 young age, and the difficulties of = conducting complex=20 endocrinological and/or neurofunctional tests at peripheral treatment = centres.=20 As paediatric oncologists, we are obliged to face a number of issues = relating to=20 the final outcome of our patients with low-grade glioma, who may be = referred for=20 diagnosis under emergency conditions with life-threatening disease in = cases of=20 diencephalic syndrome, or with slow-growing disease, as is more often = the case=20 of patients with NF1 [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR21">21</A></CITE>].=20 This latter subset of patients is, per se, at risk of developing = subsequent=20 tumours, including juvenile chronic myelomonocytic leukaemia [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR22">22</A></CITE>].=20 We are therefore very cautious, on the one hand, about when and how to = treat=20 these children, being aware that they have a long life ahead of them and = risk=20 suffering from side-effects; on the other hand, when we do decide to = start=20 treating them, it is best to adopt an effective and possibly definitive=20 strategy, based on disease control at three years documented in over 90% = of our=20 patients. Children with NF1 warrant close haematological follow-up even = though=20 secondary leukaemia after epipodophyllotoxins has not been associated = with any=20 genetic predisposition, including germline NF1 mutations. We also = substantially=20 lowered the cumulative dose of etoposide, adopted a =93moderate=94 = dosage with a low=20 correlated risk of secondary leukaemia, as defined by the NCI in their = analysis=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR23">23</A></CITE>],=20 but still risky when coupled with platinum compounds [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR24">24</A></CITE>].=20 In most patients whose disease is diagnosed at over one = year of age,=20 a low-grade glioma is more like a chronic condition than a true tumour = with a=20 definite beginning and end of the time when it is a threat to life, so = we are=20 also obliged to prevent our treatments from harming our patients. We = have, in=20 fact, demonstrated that a good response rate can be maintained with a=20 cisplatin/etoposide regimen, achieving a satisfactory PFS, and the = dosage of=20 these drugs (by comparison with the original cisplatin/etoposide = schedule) can=20 be safely reduced together with the related risk of ototoxicity in a = significant=20 number of patients. We are also confident that our treatment did not = cause any=20 significant cognitive impairment in our patients, as already = demonstrated in 18=20 patients in our former series with chiasmatic-hypothalamic tumours = [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR25">25</A></CITE>].=20 In conclusion, we can confirm that the cisplatin/etoposide = regimen=20 is equally effective at lower cumulative doses, which coincide with a = lower=20 haematological and audiological toxicity. This regimen should be = intensified for=20 metastatic tumours, however, and it is not indicated for the fibrillary=20 histotype. If some concerns remain for the risk correlated with = cumulative=20 doses of these drugs and their potential toxic effects that are not = reduced to=20 zero, we have also to remember that over 90% of survivors were never = irradiated=20 at five years of observation, thus escaping from the very well known=20 neuro-cognitive, endocrine, and oncogenic additive risks of this = adjuvant=20 treatment. Apart from this and other effective chemotherapy regimens, = however,=20 new radiotherapeutic and neurosurgical techniques have now become a = reality for=20 the treatment of these tumours (albeit only at referral centres for the = time=20 being) and paediatric neuro-oncologists need to be aware of these new=20 possibilities and always discuss their cases in a multidisciplinary = setting in=20 order to give patients every chance of suitable treatment [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR26">26</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR28">28</A></CITE>].=20 </DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgements <SPAN=20 class=3D"">This paper was presented in part at the ISPNO, 13th = International=20 Symposium on Pediatric Neuro-Oncology: June 29=96July 2, 2008 Chicago, = USA. This=20 paper was partly financed by the AIRC (Associazione Italiana per la = Ricerca sul=20 Cancro) and Associazione Bianca Garavaglia (Busto Arsizio, = Varese).</DIV> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Packer RJ, Lange B, Ater J, Nicholson HS, = Allen J,=20 Walker R, Prados M, Jakacki R, Reaman G, Needles MN (1993) = Carboplatin and=20 vincristine for recurrent and newly diagnosed low-grade gliomas of = childhood. 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From: Subject: 10.1007/s11060-010-0136-6 Date: Tue, 6 Apr 2010 21:53:08 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CAD5D3.8B12C7C0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CAD5D3.8B12C7C0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/c34647v88t66m727/fulltext.html 10.1007/s11060-010-0136-6</TIT= LE> <META http-equiv=3DContent-Type content=3D"text/html; = charset=3DISO-8859-1"><LINK=20 href=3D"http://www.springerlink.com/config/css/A++_common.css" = type=3Dtext/css=20 rel=3DstyleSheet><LINK=20 href=3D"http://www.springerlink.com/config/css/content_A++_SpringerLink.c= ss"=20 type=3Dtext/css rel=3DstyleSheet> <META content=3D"MSHTML 6.00.6000.17023" name=3DGENERATOR></HEAD> <BODY class=3Dfor-print> <TABLE cellPadding=3D2 border=3D1> <TBODY> <TR class=3Dheader> <TD>Journal of Neuro-Oncology</TD></TR> <TR> <TD>=A9 Springer Science+Business Media, = LLC. 2010</TD></TR> <TR> <TD>10.1007/s11060-010-0136-6</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>A lower-dose, lower-toxicity=20 cisplatin=96etoposide regimen for childhood progressive low-grade glioma = </DIV> Maura Massimino1 <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/contact.gif" = border=3D0></A>, Filippo Spreafico1,=20 Daria Riva5, Veronica Biassoni1,=20 Geraldina Poggi7, Carlo Solero6,=20 Lorenza Gandola2, Lorenzo Genitori8,=20 Piergiorgio Modena4, Fabio Simonetti1,=20 Paolo Potepan3, Michela Casanova1,=20 Cristina Meazza1, = Carlo A. Clerici1,=20 Serena Catania1, Iacopo Sardi8 and=20 Felice Giangaspero9 <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff1></A>(1) </TD> <TD>Division of Paediatrics, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff2></A>(2) </TD> <TD>Division of Radiotherapy, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff3></A>(3) </TD> <TD>Division of Radiology, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff4></A>(4) </TD> <TD>Molecular Biology Unit, Fond. IRCCS = Istituto=20 Nazionale Tumori, Via Venezian 1, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff5></A>(5) </TD> <TD>Department of Developmental Neurology, = Fond.=20 IRCCS Istituto Neurologico C. Besta, Via Celoria, = 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff6></A>(6) </TD> <TD>Neurosurgery Unit, Fond. IRCCS = Istituto=20 Neurologico C. Besta, Via Celoria, 20133 Milan,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff7></A>(7) </TD> <TD>Acquired Lesions Division Unit, = Istituto=20 Eugenio Medea, Via Don Luigi Monza, 20, 23842 Bosisio Parini, = Lecco,=20 Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff8></A>(8) </TD> <TD>Neurosurgery Unit, Osp. Meyer, Viale=20 Pieraccini, 24-50139 Florence, = Italy</TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><A = name=3DAff9></A>(9) </TD> <TD>Neuropathology (FG) Unit, University = La=20 Sapienza 00151 Roma and Neuromed, Via Atinense, = 18-86077 Pozzilli,=20 IS, Italy</TD></TR></TBODY></TABLE> <A name=3DContactOfAuthor1></A> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/c34647v88t66m727/contact.gif" = border=3D0></TD> = <TD>Maura Massimino</STRON= G> Email:=20 <A=20 = href=3D"mailto:maura.massimino@istitutotumori.mi.it">maura.massimino@isti= tutotumori.mi.it</A></TD></TR></TBODY></TABLE> Received:=20 23 November 2009 Accepted:=20 25 January 2010 Published online:=20 12 February 2010 <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract After successfully = using=20 cisplatin (30 mg/m2/day) and etoposide=20 (150 mg/m2/day) in ten three-day courses for progressive = low-grade gliomas, a subsequent protocol reduced the daily doses of = cisplatin=20 (to 25 mg) and etoposide (to 100 mg), with the objective of = achieving=20 the same response and three-year PFS rates with lower neurotoxicity and=20 myelotoxicity. We treated 37 patients (median age 6 years); 23 had=20 optochiasmatic tumours and nine were metastatic cases. Diagnoses were = clinical=20 in 13 cases and histological in 24, and comprised: pilocytic astrocytoma = (17),=20 ganglioglioma (3), pilomyxoid astrocytoma (2), and fibrillary = astrocytoma (2).=20 Treatment was prompted by radiological evidence of progression and/or = clinical=20 deterioration a median 18 months after the first diagnosis. After = initial=20 MRI staging, neurological and clinical examinations were performed = before each=20 chemotherapy cycle, with MRI after the first three courses and every = three=20 months thereafter. After a median 48 months, a volume reduction was = appreciable in 24 cases (65%) and response was maximum 12 months = after=20 starting treatment. The three-year EFS and OS rates were 65 and 97%,=20 respectively. Clinical, neurological, or functional improvements were = seen in=20 26/37 cases. No children had a WBC nadir below 2,000/mm3.=20 Audiological toxicity caused damage in 4/34 cases. The previous protocol = had=20 achieved volume reductions in 70% of cases, causing audiological damage = (data=20 updated) in 11/31 (P =3D 0.023), with three-year PFS = and OS rates=20 of 70 and 100%, respectively. Lower doses of cisplatin/etoposide are = still=20 effective in progressive low-grade glioma, with less acute and = persistent=20 morbidity. </DIV> Keywords Childhood=20 low-grade glioma - Chemotherapy for brain=20 tumours - Ototoxicity - Tumour = response - Symptom=20 amelioration <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> For 20 years chemotherapy has been used in children = with=20 inoperable progressive low-grade glioma (LGG) or large symptomatic = tumours with=20 a view to delaying radiotherapy, especially in younger patients with = large=20 tumours or diencephalic syndrome [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR1">1</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR3">3</A></CITE>].=20 Many schedules have been described, mainly including carboplatin, = vincristine,=20 etoposide, nitroso ureas, cisplatin, actinomycin-D, cyclophosphamide,=20 procarbazine, 6-thioguanine [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR1">1</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR4">4</A></CITE>],=20 and, more recently, vinblastine [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR5">5</A></CITE>]=20 and imatinib [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR6">6</A></CITE>].=20 Having obtained satisfactory results with a regimen of = cisplatin=20 (30 mg/m2/day) and etoposide = (150 mg/m2/day) in=20 ten three-day courses [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR7">7</A></CITE>],=20 we launched a new institutional protocol with lower daily doses of both = drugs.=20 The design of the protocol was a non-inferiority study = whose=20 primary objectives were to maintain the same rates of response and = three-year=20 progression-free survival with lower neurotoxicity (based on audiograms = or other=20 age-tailored acoustic tests) and myelotoxicity. We report the results = obtained=20 in this new series of patients. </DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Patients and methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Eligibility</DIV> All children under 18 years of age with radiological = or=20 symptomatic evidence of inoperable progressive low-grade glioma were = eligible=20 for treatment irrespective of their age or the tumour=92s origin and=20 dissemination. Histology of low-grade glioma classified according to WHO = was=20 required except in cases of optochiasmatic tumours in NF1, or when = surgery was=20 considered dangerous and the clinical and radiological signs clearly = pointed to=20 a low-grade glioma. Previous chemotherapy treatment, apart from = steroids, was=20 not allowed. </DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Chemotherapy schedule</DIV> Cisplatin was given as a 2-h infusion at=20 25 mg/m2/day on days 1=963, followed by etoposide = infused in=20 30 min at a dose of 100 mg/m2/day, again on days = 1=963; the=20 drugs were preceded and followed by a 2-h hydration. In children under = one year=20 old or weighing less than 10 kg, the doses were adjusted to their = weight.=20 The interval between cycles lasted four weeks for the first four cycles, = five=20 weeks for the next three cycles, and six weeks for the last three, = aiming to=20 cover a period of approximately 10=9611 months with 10 cycles in = all, giving=20 total doses of 750 mg/m2 cisplatin and=20 3,000 mg/m2 etoposide. The protocol was approved by our institution=92s ethical = and=20 scientific committee, and formal consent was obtained from the = patients=92=20 parents. The therapy was always administered on an outpatient = basis, except=20 for the first course, which was given during a hospital stay if the = patient was=20 fitted with a central venous catheter. </DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Evaluation of response</DIV> Initial staging included magnetic resonance imaging (MRI) = of the=20 brain and spine in all patients. When multiple sites of disease emerged = at MRI,=20 cytology of the spinal fluid was performed. Follow-up during the = treatment was=20 based on neurological and clinical assessments before each chemotherapy = cycle,=20 plus MRI of the tumour site after the first three cycles, then every = three=20 months thereafter for the first year. Tumour volume was calculated from=20 T2-weighted and enhanced T1-weighted MRI scans. Thorough neurological = and=20 clinical assessments were repeated every four months for the first three = years=20 after completing the treatment, then every six months up to the fifth = year, then=20 yearly. In the event of neurofunctional impairment, specific tests = (visual field=20 and acuity, visual-evoked potentials (VEP)) were prescribed at the same = time as=20 the radiological evaluation. Visual field assessments and visual-evoked=20 potentials were obtained at six-month intervals, wherever feasible, with = audiometric evaluation (vocal, behavioural audiometry, auditory = brainstem=20 responses or acoustic oto-emission testing, depending on the patient=92s = age)=20 during the first five years after the glioma was diagnosed. = Endocrinological=20 tests were also performed routinely and repeated if a patient showed = clinical=20 signs of any endocrinological changes. Radiological response was = assessed=20 according to International Society of Paediatric Oncology criteria and=20 protocols, i.e. complete response was defined as no evidence of disease, = partial=20 response meant a more than 50% radiographically evident size reduction, = and=20 stable disease meant no signs of tumour progression. We also considered=20 objective response, i.e. a 25=9650% size reduction in unequivocal = residual tumour=20 (the product of the two largest perpendicular diameters) [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR8">8</A></CITE>].=20 All MRI were reviewed by one of the authors (PP). All patients were = still being=20 actively followed up at the time of this report. </DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Toxicity evaluation</DIV> Audiotoxicity was monitored in all patients during the = treatment=20 using full-tone audiometry, acoustic potentials, or acoustic = oto-emission=20 testing (depending on their age) and then as explained in the previous = paragraph=20 after the treatment ended. When full-tone audiometry was feasible, the = rules for=20 stopping the treatment because of toxicity were those commonly adopted = for=20 medulloblastoma treated with a regimen containing platinum; audiometry = was=20 performed before every treatment course in children with NF1 and after = two or=20 three courses in the others. In the case of a loss of perception beyond=20 40 dB at 4,000=968,000 Hz, the cisplatin was to be replaced = with=20 carboplatin at a dose of 400 mg/m2 on the first day of = the next=20 course. In the absence of standard criteria for stopping chemotherapy in = the=20 light of other ototoxicity tests, all other patients were assessed case = by case.=20 </DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Statistical analysis</DIV> Life tables were obtained for all patients. Overall and = event-free=20 survival rates were calculated according to the Kaplan=96Meier method = [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR9">9</A></CITE>].=20 Class comparisons were drawn using the log-rank test. </DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Results</DIV> Patient accrual lasted from November 2001 to December = 2007; 22 males=20 and 15 females were enrolled; the median age was 72 months (range=20 6=96198 months) at the time of their treatment. Median follow-up at = the time=20 of writing of this report was 48 months. <DIV class=3DPara> <DIV class=3D"">The main demographic features of this series are given = in=20 Table <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Tab1">1</A>.<A=20 name=3DTab1></A> <DIV class=3DCapt>Table 1 Main=20 demographic features of the series </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> Patient</TH> <TH align=3Dleft> Sex</TH> <TH align=3Dleft char=3D"."> Age</TH> <TH align=3Dleft> Histology</TH> <TH align=3Dleft> NF1</TH> <TH align=3Dleft> Site</TH> <TH align=3Dleft> Meta</TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> 1</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 2</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Multi-nodular</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 3</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 10.08</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 4</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 3.09</TD> <TD align=3Dleft> Fibrillary</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 5</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 1.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 6</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 9.03</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 7</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.07</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 8</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 0.07</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 9</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> Fibrillary</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 10</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 13.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 11</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 12</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 0.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 13</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 14.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Temporal</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 14</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 0.05</TD> <TD align=3Dleft> Pilomixoid</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 15</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 12.00</TD> <TD align=3Dleft> Ganglioglioma</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 16</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 2.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 17</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 0.06</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 18</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 19</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 11.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 20</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 2.00</TD> <TD align=3Dleft> Ganglioglioma</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Multi-nodular</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 21</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 22</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 23</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 1.10</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 24</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 25</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 12.06</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 26</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.10</TD> <TD align=3Dleft> Ganglioglioma</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 27</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 6.05</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 28</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 29</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 13.02</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 30</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 2.06</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Mesencephalo-thalamic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 31</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 7.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 32</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 6.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> y</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 33</TD> <TD align=3Dleft> m</TD> <TD align=3Dchar char=3D"."> 1.04</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Pan-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 34</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 7.10</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 35</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 4.02</TD> <TD align=3Dleft> Pilomixoid</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Cervico-medullary</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 36</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 1.00</TD> <TD align=3Dleft> Pilocytic</TD> <TD align=3Dleft> n</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> 37</TD> <TD align=3Dleft> f</TD> <TD align=3Dchar char=3D"."> 4.01</TD> <TD align=3Dleft> </TD> <TD align=3Dleft> y</TD> <TD align=3Dleft> Opto-chiasmatic</TD> <TD align=3Dleft> n</TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D"">y, yes; n, no</DIV></DIV></DIV></DIV></DIV> When chemotherapy was begun, all the children were = suffering from=20 radiologically evident progressive disease and/or worsening symptoms; = the median=20 time from the tumour=92s diagnosis to the start of the treatment was=20 18 months (range 1 month=9610 years). Seven children had=20 neurofibromatosis type 1 (NF1) and one other child had an unknown = neurocutaneous=20 syndrome with cervico-medullary glioma, spinal and subcutaneous lipomas = and=20 mental retardation; all the other patients had sporadic tumours. <DIV class=3DPara> <DIV class=3D"">The tumour originated in the = optochiasmatic=96diencephalic region in=20 23 cases: 22 children had a Dodge 3 extension and one had a Dodge 1 = tumour. Five=20 children had tumours in the cervico=96medullary region, five gliomas = were=20 mesencephalo=96thalamic, two were multinodular with no clear primary = site, one=20 glioma occupied the whole spine, and one was temporal. In all, nine = children=20 presented with nodular metastases and one had a diagnosis of NF1. All = patients=20 with metastases had secondary nodules evident first in the brain, and=20 subsequently confirmed by MRI in the spine, except for one girl who had = sciatic=20 nerve pain prompting spinal MRI (Fig. <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig1">1</A>).=20 Liquoral seeding was never documented by cephalo=96spinal cytology. = Twenty-four=20 children underwent surgery (partial tumour resections in 18 cases and = biopsies=20 in six), enabling a histological diagnosis in all cases. The centrally = reviewed=20 (FG) histological diagnoses were: pilocytic astrocytoma in 17 cases, = pilomyxoid=20 astrocytoma in two, ganglioglioma in three, and fibrillary astrocytoma = in two.=20 The diagnoses were concordant in 22/24 cases, and two tumours previously = diagnosed as grade 3 astrocytoma were downgraded to pilocytic = astrocytoma. The=20 other 13 children were diagnosed on clinical grounds alone: 12 had=20 optochiasmatic tumours and one was a 23-month-old child with a = cervico=96medullary=20 tumour who had a recent history of rapid loss of limb strength and gait=20 competence and was sent urgently for primary adjuvant treatment after a=20 multidisciplinary discussion concluded that a low-grade glioma was = highly=20 likely. The signs and symptoms prompting these diagnoses were eyesight=20 deficiencies in 23 cases, pyramidal deficiencies in 15, diencephalic = syndrome in=20 four, cranial nerve palsy in two, monolateral proptosis in one and = intractable=20 seizures in one. Other functional alterations were early puberty in = three cases=20 and panhypopituitarism in three, obesity in one, and isolated growth = hormone=20 deficiency in one; one child developed diabetes insipidus after surgery. = <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2010_136_Fig1_HTML.jpg=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/MediaObjects/= 11060_2010_136_Fig1_HTML.jpg"></DIV> <DIV class=3DCapt>Fig. 1 Chiasmatic/metastatic=20 tumour </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV class=3D"">After chemotherapy, radiology revealed tumour reductions = in 24/37=20 cases, meeting the criteria for partial remission in 17 of these and of = complete=20 remission in one. To date, the maximum response was recorded a median=20 12 months (range 2=9631 months) after starting the treatment.=20 Table <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Tab2">2</A>=20 shows how the main signs and symptoms evolved during and after the = treatment. As=20 for sight impairments, 17/23 children with optochiasmatic tumours could = be=20 assessed adequately with consistent tests at the start and end of the=20 chemotherapy, as explained above: seven improved and the other ten were = stable;=20 of the six remaining patients, three could only undergo behavioural = sight=20 evaluation at the beginning of their course of chemotherapy, and were = judged to=20 have improved during and after treatment, whereas two were blind after = surgery=20 and one only underwent an instrumental assessment at the end of the = treatment=20 because of non-compliance.<A name=3DTab2></A> <DIV class=3DCapt>Table 2 Main = signs and=20 symptoms evolving during and after treatment </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Sight deficits 23</TD> <TD align=3Dleft> Improvement 7, stable others</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Diencephalic syndrome 4</TD> <TD align=3Dleft> Improvement 4</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Proptosis 1</TD> <TD align=3Dleft> Improvement 1</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Pyramidal deficits 15</TD> <TD align=3Dleft> Improvement 12 Stable 1 Worse 2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Cran.nerves palsy 2</TD> <TD align=3Dleft> Improvement 2</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> Seizures 1</TD> <TD align=3Dleft> Improvement 1</TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> As a total, of 37</TD> <TD align=3Dleft> Improvement 26 Stable 9 Worse 2</TD></TR></TBODY></TABLE></DIV></DIV> <DIV class=3DPara> <DIV class=3D"">Three-year progression-free survival (PFS) and overall = survival=20 (OS) were 65.5 =B1 8.5 and 97 =B1 3%, respectively, = for all=20 patients (Fig. <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig2">2</A>);=20 five-year PFS and OS were 60 =B1 9.6 and = 86.4 =B1 8%,=20 respectively. For the purposes of this report, we updated the follow-up = on all=20 28 patients in our first reported series who had not been pre-treated, = whose=20 median follow-up was 113 months: their three-year PFS was = 86 =B1 7%=20 and their OS 96 =B1 3.5% (P ns); their five-year PFS = and OS were=20 74.5 =B1 8.3 and 96 =B1 3.5%, respectively. If we = compare only=20 the patients without metastatic deposits in the two series, the = three-year PFS=20 rates are 85 =B1 7% for the first series and = 75 =B1 9% for the=20 second (P ns), and the three-year OS are 96.3 =B1 4 and = 96.3 =B1 3%.=20 <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2010_136_Fig2_HTML.gif=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/MediaObjects/= 11060_2010_136_Fig2_HTML.gif"></DIV> <DIV class=3DCapt>Fig. 2 Fig <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig1">1</A>=20 PFS and OS for the whole series </DIV> <HR> </DIV></DIV> So far, 13 children have had adverse events, occurring a = median=20 26 months after starting the treatment. Tumours progressed in 12 = children=20 and one (the child with mental retardation and an unidentified = neurocutaneous=20 syndrome) died of ab ingestis pneumonia while on the treatment. = Another=20 four children died 39, 49, 61, and 62 months after starting the = treatment,=20 two because of tumour bleeding after re-surgery, one of a glioblastoma=20 developing 44 months after irradiation for fibrillary astrocytoma=20 progression, and one while on radiotherapy for rapid tumour progression; = one=20 other child developed a glioblastoma 14 months after radiotherapy = for a=20 progressive fibrillary astrocytoma. Tumour progression was local in nine = patients and in metastatic nodules in three, all of whom had already = presented=20 with metastases at the time of their diagnosis. Radiation-free survival for the 32 surviving children was=20 94 =B1 4.3% at both three and five years. <DIV class=3DPara> <DIV class=3D"">Children with metastatic disease had a significantly = lower=20 three-year PFS, i.e. 39 =B1 17% as opposed to = 75 =B1 9% in those=20 without metastases (P =3D 0.0149; Fig. <A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#Fig3">3</A>).=20 <DIV class=3DFigure><A name=3DFig3></A><IMG=20 alt=3DMediaObjects/11060_2010_136_Fig3_HTML.gif=20 src=3D"http://www.springerlink.com/content/c34647v88t66m727/MediaObjects/= 11060_2010_136_Fig3_HTML.gif"></DIV> <DIV class=3DCapt>Fig. 3 PFS for = cases=20 with/without metastases </DIV> <HR> </DIV></DIV> In univariate analysis, age under 12 months or over = five years,=20 NF1, gender, tumour originating in the optochiasmatic region, and = debulking=20 surgery as opposed to biopsy had no statistical effect on PFS or OS. It = is worth=20 emphasizing, however, that only one of the seven children with NF1 has = relapsed=20 so far and this child had ubiquitous tumour deposits at diagnosis. On = pooling=20 our first and second series, the three-year PFS for 15 children with NF1 = was=20 93 =B1 6% and their OS was 100%. <DIV class=3D""><A name=3DSec9></A> <DIV class=3DHeading3>Toxicity</DIV> The leukocyte nadir was always above = 2.0 =D7 109/l after the=20 first course of treatment and was, consequently, not checked again = between=20 courses. No infections were documented. None of the children had to stop = the=20 treatment because of toxicity. Audiological toxicity was evaluated according to the Brock = grading=20 system [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR10">10</A></CITE>]=20 after completing all the planned treatment in 34 children: grade 1 = audiological=20 damage was documented in one child, grade 0 in two, and acoustic = potential=20 deficiencies in one. For both the patients graded as 0, this meant a = 20 dB=20 loss at 4,000 Hz. In our first series, damage had been recorded in = 11/31=20 cases, classified as grade 1 in six, grade 2 in three and grade 0 in two = (P =3D 0.023); the toxicity in the two patients graded = as 0 meant=20 a 20 dB loss at 8,000 Hz in both cases. All patients were assessed by a psychiatrist at diagnosis = and=20 tailored rehabilitation was provided, as appropriate. Endocrine tests = were=20 included in the diagnostic work-up and in the subsequent follow-up.=20 </DIV></DIV> <DIV class=3D""><A name=3DSec10></A> <HR> <DIV class=3Dheading2>Discussion</DIV> In previous reports on the efficacy of chemotherapy in = preventing=20 the progression or inducing the regression of paediatric low-grade = gliomas, many=20 authors describe institutional, national, or international trials using=20 different drug combinations given to cases inoperable because of the = site,=20 diffusion, or the clinical aggressiveness of the disease (i.e. rapid = recurrence=20 after surgery), or when radiotherapy was considered too harmful in view = of the=20 tumour=92s extent and the patient=92s young age [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR1">1</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR4">4</A></CITE>].=20 Given that most children presenting with the = above-described=20 features have tumours arising in visual pathways, causing more or less = severe=20 eyesight deficiencies, we were concerned to find that, although good = results=20 were achieved in terms of tumour response and PFS in our first reported = series=20 treated with cisplatin and etoposide, 28% of these children developed = hearing=20 impairments [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR7">7</A></CITE>].=20 Another issue was the potentially cumulative toxicity of etoposide, = especially=20 in patients with neurofibromatosis. Hence this second trial using substantially reduced doses = of=20 cisplatin (17% less) and etoposide (34% less). We recorded much the same results, in terms of three-year = PFS and=20 OS, as in the earlier series of patients: the tumour (evaluated using = the same=20 criteria in the two series) shrank in 20/28 patients in the first series = and in=20 24/37 in the second, confirming a very similar response. The time to = maximum=20 response differed substantially between the two series, however, being a = median=20 8 months for the first and 12 months for the second, prompting = us to=20 suggest that cumulative quantities of cisplatin (around=20 700=96750 mg/m2) and etoposide (around=20 3,000=963,600 mg/m2) are needed to obtain the maximum = response=20 with this regimen. We also deduce that higher cumulative doses are = responsible=20 for greater toxicity, but fail to improve or extend tumour response. = Unlike our=20 earlier series [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR7">7</A></CITE>],=20 no prognostic significance emerged from our second series for patients = below one=20 year old or over five years old. A possible explanation of this = discrepancy=20 might lie in the different numbers after subgroup stratification, i.e. = there=20 were more over five-year-olds and fewer under one-year-olds in our = second=20 series. It is also worth mentioning that our second series = included an=20 unusually large proportion of patients with metastases=97over 24% of all = the=20 consecutively treated children=97whereas the rates reported in the = literature are=20 under 10%, even in these modern times of MRI [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR11">11</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR12">12</A></CITE>].=20 The PFS rate was significantly lower for the subgroup of metastatic = patients,=20 despite 7/9 of them responding to the treatment. This emphasizes the = need to=20 find a different approach, possibly including other drugs, if genetics = succeed=20 in revealing a particular profile for tumours with this pattern of = presentation,=20 as recently demonstrated for pilocytic astrocytoma originating at other = sites=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR13">13</A></CITE>].=20 In our experience, the two children with fibrillary = astrocytoma=20 fared very badly, their tumour evolving into glioblastoma. According to = the=20 recent literature, grade 1 and grade 2 astrocytoma are clearly = distinguishable=20 at the molecular level in children [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR15">15</A></CITE>]=20 and in adults, so a tumour=92s evolution from fibrillary astrocytoma to=20 glioblastoma may be related to radiotherapy or it may be spontaneous, as = is more=20 often the case in adults [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR16">16</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR18">18</A></CITE>].=20 In our two fibrillary astrocytoma cases the IDH1 mutation, that = correlates with=20 adult low-grade glioma evolution into glioblastoma, was not found. The rapid disease progression and death of a third patient = with a=20 pilocytic astrocytoma of the visual pathway (presenting with huge = metastases=20 already at diagnosis) was rather unexpected, although there are reports = of=20 similar evolution in the literature and the recent histopathological=20 stratification of pilocytic astrocytoma can clarify such cases with a=20 particularly poor outcome [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR19">19</A></CITE>].=20 In addition to the radiological response, we also = considered the=20 signs and symptoms prompting our patients=92 diagnosis, which improved = in 70% of=20 cases. As Gutmann also pointed out, given the slow growth rate and = infiltrative=20 nature of low-grade glioma in children, a reduction in overall tumour = volume=20 cannot be the only endpoint of clinical trials on these diseases = [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR20">20</A></CITE>].=20 Changes in clinical variables may be very difficult to assess [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR4">4</A></CITE>]=20 because, for example, of the lack of standardized methods of = ophthalmological=20 evaluation, the patients=92 young age, and the difficulties of = conducting complex=20 endocrinological and/or neurofunctional tests at peripheral treatment = centres.=20 As paediatric oncologists, we are obliged to face a number of issues = relating to=20 the final outcome of our patients with low-grade glioma, who may be = referred for=20 diagnosis under emergency conditions with life-threatening disease in = cases of=20 diencephalic syndrome, or with slow-growing disease, as is more often = the case=20 of patients with NF1 [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR21">21</A></CITE>].=20 This latter subset of patients is, per se, at risk of developing = subsequent=20 tumours, including juvenile chronic myelomonocytic leukaemia [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR22">22</A></CITE>].=20 We are therefore very cautious, on the one hand, about when and how to = treat=20 these children, being aware that they have a long life ahead of them and = risk=20 suffering from side-effects; on the other hand, when we do decide to = start=20 treating them, it is best to adopt an effective and possibly definitive=20 strategy, based on disease control at three years documented in over 90% = of our=20 patients. Children with NF1 warrant close haematological follow-up even = though=20 secondary leukaemia after epipodophyllotoxins has not been associated = with any=20 genetic predisposition, including germline NF1 mutations. We also = substantially=20 lowered the cumulative dose of etoposide, adopted a =93moderate=94 = dosage with a low=20 correlated risk of secondary leukaemia, as defined by the NCI in their = analysis=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR23">23</A></CITE>],=20 but still risky when coupled with platinum compounds [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR24">24</A></CITE>].=20 In most patients whose disease is diagnosed at over one = year of age,=20 a low-grade glioma is more like a chronic condition than a true tumour = with a=20 definite beginning and end of the time when it is a threat to life, so = we are=20 also obliged to prevent our treatments from harming our patients. We = have, in=20 fact, demonstrated that a good response rate can be maintained with a=20 cisplatin/etoposide regimen, achieving a satisfactory PFS, and the = dosage of=20 these drugs (by comparison with the original cisplatin/etoposide = schedule) can=20 be safely reduced together with the related risk of ototoxicity in a = significant=20 number of patients. We are also confident that our treatment did not = cause any=20 significant cognitive impairment in our patients, as already = demonstrated in 18=20 patients in our former series with chiasmatic-hypothalamic tumours = [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR25">25</A></CITE>].=20 In conclusion, we can confirm that the cisplatin/etoposide = regimen=20 is equally effective at lower cumulative doses, which coincide with a = lower=20 haematological and audiological toxicity. This regimen should be = intensified for=20 metastatic tumours, however, and it is not indicated for the fibrillary=20 histotype. If some concerns remain for the risk correlated with = cumulative=20 doses of these drugs and their potential toxic effects that are not = reduced to=20 zero, we have also to remember that over 90% of survivors were never = irradiated=20 at five years of observation, thus escaping from the very well known=20 neuro-cognitive, endocrine, and oncogenic additive risks of this = adjuvant=20 treatment. Apart from this and other effective chemotherapy regimens, = however,=20 new radiotherapeutic and neurosurgical techniques have now become a = reality for=20 the treatment of these tumours (albeit only at referral centres for the = time=20 being) and paediatric neuro-oncologists need to be aware of these new=20 possibilities and always discuss their cases in a multidisciplinary = setting in=20 order to give patients every chance of suitable treatment [<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR26">26</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/c34647v88t66m727/fulltext.htm= l#CR28">28</A></CITE>].=20 </DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgements <SPAN=20 class=3D"">This paper was presented in part at the ISPNO, 13th = International=20 Symposium on Pediatric Neuro-Oncology: June 29=96July 2, 2008 Chicago, = USA. 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