10.1007/s11060-009-9980-7</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 6.00.6000.16890" 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 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-9980-7</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Extended-schedule dose-dense = temozolomide=20 in refractory gliomas </DIV> <P class=3DAuthorGroup>A. Berrocal<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/p11524720808612w/contact.gif" = border=3D0></A></SUP>, P. Perez Segura<SUP>2</SUP>, = M. Gil<SUP>3</SUP>,=20 C. Bala=F1a<SUP>4</SUP>, J. Garcia Lopez<SUP>5</SUP>,=20 R. Yaya<SUP>6</SUP>, J. Rodr=EDguez<SUP>7</SUP>,=20 G. Reynes<SUP>8</SUP>, O. Gallego<SUP>9</SUP>,=20 L. Iglesias<SUP>10</SUP> and GENOM Cooperative Group<SUP></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Servicio de Oncologia Medica, = Consorcio=20 Hospital General Universitario de Valencia, Avda Tres Cruces S/N,=20 46006 Valencia, Spain</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>Hospital Clinico San Carlos, Madrid,=20 Spain</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>Instituto Catalan de Oncologia Duran i = Reynals, Barcelona, Spain</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>Hospital Germans Trias i Pujol, = Badalona,=20 Spain</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>Hospital Ramon y Cajal, Madrid,=20 Spain</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>Instituto Valenciano de Oncologia, = Valencia,=20 Spain</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>Hospital de Sondureta, Palma de = Mallorca,=20 Spain</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>Hospital La Fe, Valencia,=20 Spain</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>Hospital Santa Creu i San Pau, = Barcelona,=20 Spain</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Hospital Virgen del Rocio, Sevilla,=20 Spain</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/p11524720808612w/contact.gif" = border=3D0></TD> = <TD><STRONG>A. </STRONG><STRONG>Berrocal</STRONG><STRONG></STRONG><B= R><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:berrocal_alf@gva.es">berrocal_alf@gva.es</A></TD></TR></TB= ODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>21 May 2009 <STRONG>Accepted:=20 </STRONG>20 July 2009 <STRONG>Published online:=20 </STRONG>8 August 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>This multicenter = phase II study=20 conducted by the Spanish Neuro-Oncology Group evaluated the activity of = an=20 extended, dose-dense temozolomide regimen in patients with=20 temozolomide-refractory malignant glioma. Adult patients (at least = 18 years=20 of age) with WHO grade III or IV glioma and a Karnofsky Performance = Status of 60=20 or higher were treated with temozolomide (85 mg/m<SUP>2</SUP>/day) = for 21=20 consecutive days every 28-day cycle until disease progression or = unacceptable=20 toxicity. All patients had developed progressive disease either during = or less=20 than 3 months after completing previous temozolomide treatment. = Forty-seven=20 patients were treated with a median of 2 (range, 1=9613) cycles of = temozolomide.=20 Before study entry, patients had received a median of 6 cycles of = temozolomide:=20 39 (83%) as part of initial therapy and 23 (49%) as second-line therapy. = Three=20 patients (6.4%) had a partial response with durations of 8.0, 3.5, and=20 3.2 months; 15 patients (31.9%) had stable disease with a median = duration=20 of 2.1 months, including 2 patients with stable disease (SD) for = greater=20 than 6 months (14 and 16 months). Median time to progression = was=20 2 months, and median overall survival from study entry was = 5.1 months.=20 The 6-month progression-free survival rate was 16.7%. The most common=20 hematologic toxicities were lymphopenia, thrombocytopenia, and = leukopenia.=20 Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no=20 opportunistic infections occurred. In conclusion, this extended = dose-dense=20 schedule of temozolomide appears to have modest activity in patients = refractory=20 to previous treatment with temozolomide and is associated with = manageable=20 toxicity. </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Temozolomide -&nbs= p;Activity - Refractory - Malignant=20 glioma </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">Malignant gliomas are aggressive tumors and, despite = recent=20 improvements in their treatment, almost always relapse after first-line=20 treatment and remain incurable [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR1">1</A></CITE>].=20 The majority of patients with high-grade gliomas receive temozolomide = either as=20 first-line treatment in combination with radiotherapy or at relapse, = based on=20 evidence from prospective trials demonstrating the clinical benefit of=20 temozolomide in these settings [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR3">3</A></CITE>].=20 Temozolomide is an imidazotetrazine derivative that methylates the DNA = at=20 several sites including N<SUP>7</SUP>-guanine (70%), = N<SUP>3</SUP>-adenine (9%),=20 or O<SUP>6</SUP>-guanine (5%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR4">4</A></CITE>].=20 However, only methylation at O<SUP>6</SUP>-guanine and=20 O<SUP>6</SUP>-methylguanine DNA adducts appears to drive the cytotoxic = activity=20 of temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR5">5</A></CITE>].=20 </P> <P class=3D"">The DNA damage caused by temozolomide is repaired by=20 O<SUP>6</SUP>-methylguanine methyltransferase (MGMT), which is consumed = in the=20 process [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR6">6</A></CITE>].=20 Several studies have suggested that resistance to alkylating agents is = primarily=20 mediated by MGMT [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR6">6</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR8">8</A></CITE>].=20 Furthermore, it has been demonstrated that temozolomide decreases MGMT = activity=20 in peripheral mononuclear cells in a schedule-dependent manner [<CITE><A = href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR9">9</A></CITE>],=20 and that protracted administration of temozolomide results in more = extensive and=20 sustained depletion of MGMT [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR10">10</A></CITE>].=20 Finally, it has been demonstrated that depletion of MGMT enhances the=20 cytotoxicity of temozolomide and other alkylating agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR11">11</A></CITE>].=20 </P> <P class=3D"">Based on these observations, it is reasonable to = hypothesize that=20 extended temozolomide administration may overcome resistance through = MGMT=20 depletion and restore sensitivity to temozolomide in patients with=20 temozolomide-refractory malignant glioma. The present trial was designed = by the=20 Spanish Neuro-Oncology Group (GENOM) to test the activity of an = extended,=20 dose-dense temozolomide regimen=20 (85 mg/m<SUP>2</SUP> =D7 21 days every 28 days) = in=20 patients who had progressed following first-line or second-line = treatment with=20 temozolomide. This dose was selected based on the results of a phase I = trial in=20 patients previously treated with temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR12">12</A></CITE>].=20 </P></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>Patient eligibility</DIV> <P class=3D"">Adult patients (at least 18 years of age) with = histologically=20 confirmed, temozolomide-refractory, WHO grade III or IV glioma and a = Karnofsky=20 Performance Status (KPS) of 60 or higher were included. Patients were = eligible=20 and considered refractory to temozolomide if they developed progressive = disease=20 during temozolomide treatment or less than 3 months after = completing=20 previous temozolomide treatment. </P> <P class=3D"">Adequate laboratory values were required as follows: = absolute=20 neutrophil count ≥1,500/μl, platelet count = ≥100,000/μl, hemoglobin greater than=20 10 g/dl or 100 g/l, blood urea nitrogen and serum creatinine = less than=20 1.5 times the upper limit of laboratory normal, total and direct serum = bilirubin=20 less than 1.5 times the upper limit of laboratory normal, aspartate=20 aminotransferase or alanine aminotransferase less than 3 times the upper = limit=20 of laboratory normal, and alkaline phosphatase less than 2 times the = upper limit=20 of laboratory normal. Patients were required to have been on a = non-increasing=20 corticosteroid dose for ≥72 h before baseline neuroimaging = and study drug=20 administration, and to have a life expectancy greater than = 12 weeks. All=20 patients were required to provide written informed consent. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Study design</DIV> <P class=3D"">This was a multicenter phase II trial conducted by the = GENOM.=20 Institutional review boards at each study center approved the study. The = primary=20 objective was to assess whether an extended temozolomide dosing schedule = can=20 overcome tumor resistance to the drug. Secondary objectives were = response and=20 tolerability. According to the 2-stage model of Simon et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR13">13</A></CITE>],=20 the primary objective was considered not reached if no objective = response was=20 observed in the first 10 patients or if less than 3 responses were = observed=20 among 29 patients in the second stage. Sample size was estimated = according to=20 the Simon 2-stage phase II design (P<SUB>0</SUB> =3D 5% = response rate;=20 P<SUB>1</SUB> =3D 20% response rate) [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR13">13</A></CITE>].=20 To achieve an (α, β) error of (0.05, 0.2), a total of 29 = patients were required,=20 and to achieve an (α, β) error of (0.05, 0.1), a total of 43 = patients were=20 required. </P></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Treatment</DIV> <P class=3D"">After a 4-week clearance period to allow recovery from = toxicities,=20 patients received temozolomide at a starting dose of=20 85 mg/m<SUP>2</SUP>/day in a fasting state for 21 consecutive days = every=20 28-day cycle. Temozolomide treatment was administered until disease = progression=20 (PD) or unacceptable toxicity occurred. Three dose levels were defined:=20 85 mg/m<SUP>2</SUP>, 75 mg/m<SUP>2</SUP>, and=20 65 mg/m<SUP>2</SUP>. If neutrophils were over 1500/μl and = platelets over=20 100,000/μl patients were treated at the 85 mg/m<SUP>2</SUP> = dose;=20 otherwise, treatment was delayed for 1 week to a maximum of = 3 weeks=20 until recovery. If neutrophils were below 500/μl for 5 days, = or platelets=20 were below 25,000/μl, or if the treatment delay was greater than = 2 weeks,=20 the dose was reduced to the next lower level. If nonhematologic toxicity = of=20 grade 3 or greater occurred, the dose was also reduced. Prophylactic = antiemetic=20 therapy with metoclopramide or 5-HT antagonist was administered to all = patients.=20 No <I>Pneumocystis jirovecii</I> pneumonia prophylaxis was administered. = </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Assessment of response and safety</DIV> <P class=3D"">Response was assessed according to Macdonald=92s criteria = [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR14">14</A></CITE>].=20 Neurologic examination and steroid dose modification were recorded at = each=20 cycle. Neuroimaging with gadolinium-enhanced MRI was performed at least = every 2=20 cycles or if PD was suspected based on neurologic symptoms. Complete = response=20 was defined as complete disappearance of all detectable tumors as = determined by=20 2 gadolinium-enhanced MRI scans of the brain performed not less than=20 4 weeks apart. Adverse events were graded according to the National = Cancer=20 Institute Common Terminology Criteria for Adverse Events v3.0. = </P></DIV></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3DPara> <DIV class=3D"">A total of 47 patients were enrolled and received at = least 1 cycle=20 of temozolomide. All patients were assessable for response and safety. = Baseline=20 patient characteristics are shown in Table <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Tab1">1</A>.=20 Median time from the diagnosis to study entry was 14 months (range=20 6=96126 months). Before study entry, patients had received a median = of 6=20 (range 1=9621) cycles of temozolomide: 39 patients (83%) as part of = initial=20 therapy and 23 patients (49%) as second-line therapy. Thus, some = patients had=20 received temozolomide as part of both first- and second-line therapy. = All=20 patients had progressed during or within 3 months of completing=20 standard-dose therapy and at least 6 months after completing=20 chemoradiotherapy. No patients received dose-dense temozolomide before = study=20 entry. Anticonvulsant therapy was administered to 31 patients (66%). The = most=20 frequently used anticonvulsants were phenytoin in 17 patients (55%), = valproic=20 acid in 11 patients (36%), gabapentin in 6 patients (19%), and = levetiracetam in=20 5 patients (16%). Some patients received more than 1 anticonvulsant = drug.<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Patient = demographics=20 and baseline clinical characteristics (<I>N</I> =3D 47) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Mean age, years (range)</P></TD> <TD align=3Dleft> <P class=3D"">50 (20=9677)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Sex, <I>n</I> (%) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Male</P></TD> <TD align=3Dleft> <P class=3D"">33 (70)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Female</P></TD> <TD align=3Dleft> <P class=3D"">14 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">ECOG performance status, <I>n</I> (%) </P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 0</P></TD> <TD align=3Dleft> <P class=3D"">8 (17)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 1</P></TD> <TD align=3Dleft> <P class=3D"">20 (43)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 2</P></TD> <TD align=3Dleft> <P class=3D"">19 (40)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Tumor histology, <I>n</I> (%) </P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Glioblastoma</P></TD> <TD align=3Dleft> <P class=3D"">27 (57)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Anaplastic = astrocytoma</P></TD> <TD align=3Dleft> <P class=3D"">15 (32)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Anaplastic = oligodendroglioma</P></TD> <TD align=3Dleft> <P class=3D"">3 (6)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Other</P></TD> <TD align=3Dleft> <P class=3D"">2 (4)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Prior surgery, <I>n</I> (%) </P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Biopsy only</P></TD> <TD align=3Dleft> <P class=3D"">9 (19)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Partial resection</P></TD> <TD align=3Dleft> <P class=3D"">20 (43)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Gross total = resection</P></TD> <TD align=3Dleft> <P class=3D"">17 (36)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Biopsy and partial = resection</P></TD> <TD align=3Dleft> <P class=3D"">1 (2)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Prior first-line chemotherapy, <I>n</I> (%) = </P></TD> <TD align=3Dleft> <P class=3D""><I>n</I> =3D 47 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Temozolomide</P></TD> <TD align=3Dleft> <P class=3D"">38 (81)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Carmustine</P></TD> <TD align=3Dleft> <P class=3D"">4 (9)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> PCV</P></TD> <TD align=3Dleft> <P class=3D"">4 (9)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P=20 = class=3D""> Temozolomide + cisplatin</P>= </TD> <TD align=3Dleft> <P class=3D"">1 (2)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Prior second-line chemotherapy, <I>n</I> (%) = </P></TD> <TD align=3Dleft> <P class=3D""><I>n</I> =3D 23 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Temozolomide = monotherapy</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Temozolomide-based=20 polychemotherapy</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>ECOG</I> Eastern Cooperative Oncology Group; = <I>PCV</I>=20 procarbazine, lomustine, and vincristine </DIV></DIV></DIV></DIV></DIV> <P class=3D"">Patients received a median of 2 (range, 1=9613) cycles of = temozolomide=20 on study, and a total of 168 treatment cycles were administered. Sixteen = cycles=20 were delayed in 7 patients as a result of hematologic toxicity in 3 = patients,=20 nonhematologic toxicity in 2 patients, and for administrative reasons in = 2=20 patients. Only 3 cycles were dose reduced in 2 patients because of = hematologic=20 toxicity. </P> <P class=3D"">Among 47 treated patients, 3 (6.4%) had a partial response = (95%=20 confidence interval [CI]: 0.6%, 13.2%), including 1 patient with=20 oligodendroglioma who had received 3 previous lines of therapy, 1 = patient with a=20 glioblastoma who had received 2 previous lines of therapy, and 1 patient = with a=20 glioblastoma who had received 1 previous line of therapy. Duration of = the=20 responses was 8, 3.2, and 3.5 months, respectively. In addition, 15 = patients (31.9%) had stable disease (SD). Median duration of SD was=20 2.1 months, and 2 patients remained stable for greater than = 6 months=20 (14 and 16 months). One of 3 responders, 6 of 15 patients with SD, = and 9 of=20 30 patients with PD on study had a response or SD lasting greater than=20 6 months during previous temozolomide therapy. All 3 patients who = had a=20 response or SD lasting greater than 6 months on study also had a = response=20 or SD lasting greater than 6 months during previous temozolomide = therapy.=20 </P> <DIV class=3DPara> <DIV class=3D"">At a median follow up of 3.6 months, median time to = progression was 2 months (95% CI: 1.6, 2.4 months; = Fig. <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Fig1">1</A>)=20 and median overall survival from study entry was 5.1 months (95% = CI: 3.7,=20 6.5 months; Fig. <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Fig2">2</A>).=20 The 6-month progression-free survival (PFS) rates were 16.7% for the = overall=20 population, 0% among patients with glioblastoma, and 37.5% among = patients with=20 anaplastic astrocytoma or oligodendroglioma. The 6-month overall = survival rate=20 was 41.6% (95% CI: 25.1%, 58.1%).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_9980_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/p11524720808612w/MediaObjects/= 11060_2009_9980_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Kaplan=96Meier estimate=20 of time to progression </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_9980_Fig2_HTML.gif=20 src=3D"http://www.springerlink.com/content/p11524720808612w/MediaObjects/= 11060_2009_9980_Fig2_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 2 </SPAN>Kaplan=96Meier estimate=20 of overall survival </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV class=3D"">The most common hematologic toxicities were lymphopenia, = thrombocytopenia, and leukopenia (Table <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Tab2">2</A>).=20 Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no=20 opportunistic infections occurred. The most common nonhematologic = adverse events=20 or laboratory abnormalities were nausea/vomiting, asthenia, and mild=20 asymptomatic transaminitis (Table <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Tab3">3</A>).=20 Most nonhematologic adverse events and laboratory abnormalities were = mild to=20 moderate in severity, and there was no grade 4 toxicity.<A = name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Hematologic toxicity=20 by grade </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft rowSpan=3D2> </TH> <TH align=3Dleft colSpan=3D3 char=3D"("> <P class=3D"">Patients, <I>n</I> (%) </P></TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 1 or 2</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 3</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Total</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lymphopenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">26 (55)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">13 (28)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">39 (83)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Thrombocytopenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">5 (11)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">14 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Leukopenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">13 (28)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">14 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Anemia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">7 (15)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Neutropenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (17)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD></TR></TBODY></TABLE><A = name=3DTab3></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 3 </SPAN>Most = common=20 nonhematologic adverse events and laboratory abnormalities by grade = </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft rowSpan=3D2> </TH> <TH align=3Dleft colSpan=3D3 char=3D"("> <P class=3D"">Patients, <I>n</I> (%) </P></TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 1 or 2</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 3</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Total</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D4> <P class=3D"">Adverse events</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Nausea/vomiting</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">12 (26)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">13 (28)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Asthenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (17)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (17)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Diarrhea</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">5 (11)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">5 (11)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Constipation</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mucositis</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">3 (6)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D4> <P class=3D"">Laboratory abnormalities</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GPT</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">24 (51)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">24 (51)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GOT</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Creatinine</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">6 (13)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">6 (13)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GGT</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bilirubin</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>GPT</I> glutamic-pyruvic transaminase, <I>GOT</I>=20 glutamic-oxaloacetic transaminase, <I>GGT</I> gamma-glutamyl transferase = </DIV></DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">Since the publication of the pivotal phase III trial in = 2005=20 demonstrating the superiority of combining radiotherapy with = temozolomide=20 compared with radiotherapy alone in newly diagnosed glioblastoma = patients=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR8">8</A></CITE>],=20 temozolomide has become the standard of care for initial treatment of=20 glioblastoma and is widely used for treatment of anaplastic glioma.=20 Consequently, standard-dose temozolomide may no longer be the best = treatment=20 option at recurrence. A variety of options have been explored, including = retreatment with temozolomide using a dose-dense schedule or treatment = with=20 nitrosoureas, irinotecan, bevacizumab, or a variety of novel = combinations of=20 these and other agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR15">15</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR19">19</A></CITE>].=20 Carmustine has demonstrated only limited activity after temozolomide = [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR18">18</A></CITE>],=20 whereas irinotecan, in combination with bevacizumab, carmustine, or = thalidomide,=20 has demonstrated promising activity in this setting [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR15">15</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR19">19</A></CITE>].=20 Presumably most high-grade gliomas are refractory to alkylating agents = at=20 recurrence following initial treatment with temozolomide. However, a = recent=20 report by Perry et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR20">20</A></CITE>]=20 of interim data from the RESCUE study has shown that retreatment with = continuous=20 low-dose daily temozolomide resulted in favorable 6-month PFS rates in = patients=20 who progressed during or after first-line temozolomide. Other studies = have also=20 demonstrated the activity of dose-dense temozolomide regimens in this = setting=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR21">21</A></CITE>].=20 </P> <P class=3D"">The results of the present study have further demonstrated = that=20 retreatment with temozolomide using an extended, dose-dense schedule can = result=20 in objective responses in patients previously exposed to temozolomide as = part of=20 their initial treatment. Although the observed 6.3% partial response = rate and=20 6-month PFS rate were modest, patients enrolled in this study were = pretreated=20 with a median of 6 cycles of temozolomide, and many patients received = extended=20 treatment with up to 21 cycles of standard-dose temozolomide before = study entry.=20 Similarly, among patients enrolled in the RESCUE study, those who = received=20 prolonged maintenance therapy with standard-dose temozolomide (beyond 6 = cycles)=20 had a low 6-month PFS rate (9.5%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR20">20</A></CITE>].=20 In addition, all patients entered the present study at least = 6 months after=20 completing previous radiotherapy. This suggests that the responses = observed in=20 the present study were not an artifact of pseudoprogression, but this = cannot be=20 completely ruled out. </P> <P class=3D"">It has been observed that patients who have prolonged SD = after=20 primary temozolomide treatment often have a prolonged response to = retreatment=20 with temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>].=20 Consistent with these published reports, all patients who had a durable = response=20 or SD in the present study had previously had a durable response or SD = to first-=20 or second-line temozolomide. It should be noted, however, that objective = responses and SD have been observed in patients who had a short duration = of=20 response to first-line temozolomide. Therefore, no patient should be = excluded=20 from retreatment with an extended temozolomide regimen based on the = quality of=20 their response to first-line temozolomide. </P> <P class=3D"">Compared with the standard 5-day dosing schedule every = 28-day cycle,=20 the extended dose-dense schedules result in approximately a 2-fold = greater=20 exposure to temozolomide and may have greater potential to deplete MGMT = activity=20 within tumor cells and overcome resistance [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR11">11</A></CITE>].=20 The first report of an extended temozolomide regimen investigated a dose = of=20 75 mg/m<SUP>2</SUP>/day for 6 or 7 consecutive weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR24">24</A></CITE>].=20 This schedule resulted in a 41% response rate among 17 patients with = recurrent=20 glioma. Subsequent studies in glioblastoma investigating 2 different = extended=20 temozolomide schedules (7 consecutive days every 2 weeks, or 21 = consecutive=20 days every 28 days) showed that both schedules resulted in a = significant=20 and prolonged depletion of MGMT in peripheral blood mononuclear cells, = which led=20 to the hypothesis that these dose-dense regimens could potentially = enhance=20 antitumor activity [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR10">10</A></CITE>].=20 Two phase II trials in patients with recurrent glioblastoma also = demonstrated=20 that these regimens are highly active [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR25">25</A></CITE>].=20 In the first study conducted in temozolomide-naive patients, the 21-day=20 continuous schedule resulted in a 9% response rate and a 6-month PFS = rate of 30%=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR25">25</A></CITE>].=20 In the second study, the majority of patients had not been previously = exposed to=20 temozolomide, and the alternating weekly regimen resulted in a response = rate of=20 15% and a 6-month PFS rate of 44% [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>].=20 Therefore, the fact that 2 of 27 (7%) glioblastoma patients in the = present study=20 who were previously treated with temozolomide had an objective response = supports=20 the hypothesis that this dose-dense regimen may overcome resistance. One = limitation of the present study is the lack of data on MGMT methylation = status=20 of these tumors. However, MGMT methylation status at initial diagnosis = has=20 limited value in the recurrent setting, particularly given the = observation that=20 methylation patterns within the tumor can change from initial diagnosis = to=20 recurrence. </P> <P class=3D"">Toxicity associated with extended, dose-dense temozolomide = schedules=20 has been reported to be greater than that associated with the = conventional 5-day=20 schedule and to consist mainly of lymphopenia [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR28">28</A></CITE>].=20 In the present study, grade 3 or higher lymphopenia occurred in nearly = 30% of=20 patients. However, no complications related to immunodeficiency such as=20 <I>Pneumocystis jirovecii</I> pneumonia were reported, even in the = absence of=20 PCP prophylaxis. All toxicities were manageable, and few patients = required=20 treatment delays or dose reductions. </P> <P class=3D"">In conclusion, this extended dose-dense schedule of = temozolomide=20 appears to have activity, albeit modest, in patients who have failed = previous=20 treatment with temozolomide and is associated with manageable toxicity. = These=20 results suggest that extended schedules of temozolomide may be = preferable to the=20 standard temozolomide regimen and should be further evaluated in larger=20 randomized studies with prospective stratification of patients by = primary tumor=20 type and extent of prior temozolomide therapy. The full results of the = RESCUE=20 study are eagerly awaited and may provide further insight regarding how = best to=20 use temozolomide in the recurrent setting. </P></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments </SPAN><SPAN=20 class=3D"">Financial support for medical editorial assistance was = provided by=20 Schering-Plough International. We thank Jeffrey Riegel, PhD, ProEd=20 Communications, Inc.<SUP>=AE</SUP>, for his medical editorial assistance = with this=20 manuscript.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN> This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </DIV></DIV></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>Gilbert MR (2006) Advances in the treatment of = primary=20 brain tumors: dawn of a new era? 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From: Subject: 10.1007/s11060-009-9980-7 Date: Thu, 27 Aug 2009 21:14:26 +0200 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01CA275B.5BB164E0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01CA275B.5BB164E0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/p11524720808612w/fulltext.html 10.1007/s11060-009-9980-7</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 6.00.6000.16890" 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 The Author(s) 2009</TD></TR> <TR> <TD>10.1007/s11060-009-9980-7</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Extended-schedule dose-dense = temozolomide=20 in refractory gliomas </DIV> <P class=3DAuthorGroup>A. Berrocal<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/p11524720808612w/contact.gif" = border=3D0></A></SUP>, P. Perez Segura<SUP>2</SUP>, = M. Gil<SUP>3</SUP>,=20 C. Bala=F1a<SUP>4</SUP>, J. Garcia Lopez<SUP>5</SUP>,=20 R. Yaya<SUP>6</SUP>, J. Rodr=EDguez<SUP>7</SUP>,=20 G. Reynes<SUP>8</SUP>, O. Gallego<SUP>9</SUP>,=20 L. Iglesias<SUP>10</SUP> and GENOM Cooperative Group<SUP></SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Servicio de Oncologia Medica, = Consorcio=20 Hospital General Universitario de Valencia, Avda Tres Cruces S/N,=20 46006 Valencia, Spain</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>Hospital Clinico San Carlos, Madrid,=20 Spain</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>Instituto Catalan de Oncologia Duran i = Reynals, Barcelona, Spain</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>Hospital Germans Trias i Pujol, = Badalona,=20 Spain</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>Hospital Ramon y Cajal, Madrid,=20 Spain</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>Instituto Valenciano de Oncologia, = Valencia,=20 Spain</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>Hospital de Sondureta, Palma de = Mallorca,=20 Spain</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>Hospital La Fe, Valencia,=20 Spain</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff9></A>(9) </SPAN></TD> <TD><SPAN class=3DAffiliation>Hospital Santa Creu i San Pau, = Barcelona,=20 Spain</SPAN></TD></TR></TBODY></TABLE> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff10></A>(10) </SPAN></TD> <TD><SPAN class=3DAffiliation>Hospital Virgen del Rocio, Sevilla,=20 Spain</SPAN></TD></TR></TBODY></TABLE> <P><A name=3DContactOfAuthor1></A></P> <TABLE class=3DContact> <TBODY> <TR> <TD vAlign=3Dtop><IMG alt=3D"Contact Information"=20 = src=3D"http://www.springerlink.com/content/p11524720808612w/contact.gif" = border=3D0></TD> = <TD><STRONG>A. </STRONG><STRONG>Berrocal</STRONG><STRONG></STRONG><B= R><STRONG>Email:=20 </STRONG><A=20 = href=3D"mailto:berrocal_alf@gva.es">berrocal_alf@gva.es</A></TD></TR></TB= ODY></TABLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>21 May 2009 <STRONG>Accepted:=20 </STRONG>20 July 2009 <STRONG>Published online:=20 </STRONG>8 August 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>This multicenter = phase II study=20 conducted by the Spanish Neuro-Oncology Group evaluated the activity of = an=20 extended, dose-dense temozolomide regimen in patients with=20 temozolomide-refractory malignant glioma. Adult patients (at least = 18 years=20 of age) with WHO grade III or IV glioma and a Karnofsky Performance = Status of 60=20 or higher were treated with temozolomide (85 mg/m<SUP>2</SUP>/day) = for 21=20 consecutive days every 28-day cycle until disease progression or = unacceptable=20 toxicity. All patients had developed progressive disease either during = or less=20 than 3 months after completing previous temozolomide treatment. = Forty-seven=20 patients were treated with a median of 2 (range, 1=9613) cycles of = temozolomide.=20 Before study entry, patients had received a median of 6 cycles of = temozolomide:=20 39 (83%) as part of initial therapy and 23 (49%) as second-line therapy. = Three=20 patients (6.4%) had a partial response with durations of 8.0, 3.5, and=20 3.2 months; 15 patients (31.9%) had stable disease with a median = duration=20 of 2.1 months, including 2 patients with stable disease (SD) for = greater=20 than 6 months (14 and 16 months). Median time to progression = was=20 2 months, and median overall survival from study entry was = 5.1 months.=20 The 6-month progression-free survival rate was 16.7%. The most common=20 hematologic toxicities were lymphopenia, thrombocytopenia, and = leukopenia.=20 Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no=20 opportunistic infections occurred. In conclusion, this extended = dose-dense=20 schedule of temozolomide appears to have modest activity in patients = refractory=20 to previous treatment with temozolomide and is associated with = manageable=20 toxicity. </DIV> <P class=3DKeyword><SPAN=20 class=3DKeywordHeading>Keywords </SPAN>Temozolomide -&nbs= p;Activity - Refractory - Malignant=20 glioma </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">Malignant gliomas are aggressive tumors and, despite = recent=20 improvements in their treatment, almost always relapse after first-line=20 treatment and remain incurable [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR1">1</A></CITE>].=20 The majority of patients with high-grade gliomas receive temozolomide = either as=20 first-line treatment in combination with radiotherapy or at relapse, = based on=20 evidence from prospective trials demonstrating the clinical benefit of=20 temozolomide in these settings [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR3">3</A></CITE>].=20 Temozolomide is an imidazotetrazine derivative that methylates the DNA = at=20 several sites including N<SUP>7</SUP>-guanine (70%), = N<SUP>3</SUP>-adenine (9%),=20 or O<SUP>6</SUP>-guanine (5%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR4">4</A></CITE>].=20 However, only methylation at O<SUP>6</SUP>-guanine and=20 O<SUP>6</SUP>-methylguanine DNA adducts appears to drive the cytotoxic = activity=20 of temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR4">4</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR5">5</A></CITE>].=20 </P> <P class=3D"">The DNA damage caused by temozolomide is repaired by=20 O<SUP>6</SUP>-methylguanine methyltransferase (MGMT), which is consumed = in the=20 process [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR6">6</A></CITE>].=20 Several studies have suggested that resistance to alkylating agents is = primarily=20 mediated by MGMT [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR6">6</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR8">8</A></CITE>].=20 Furthermore, it has been demonstrated that temozolomide decreases MGMT = activity=20 in peripheral mononuclear cells in a schedule-dependent manner [<CITE><A = href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR9">9</A></CITE>],=20 and that protracted administration of temozolomide results in more = extensive and=20 sustained depletion of MGMT [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR10">10</A></CITE>].=20 Finally, it has been demonstrated that depletion of MGMT enhances the=20 cytotoxicity of temozolomide and other alkylating agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR11">11</A></CITE>].=20 </P> <P class=3D"">Based on these observations, it is reasonable to = hypothesize that=20 extended temozolomide administration may overcome resistance through = MGMT=20 depletion and restore sensitivity to temozolomide in patients with=20 temozolomide-refractory malignant glioma. The present trial was designed = by the=20 Spanish Neuro-Oncology Group (GENOM) to test the activity of an = extended,=20 dose-dense temozolomide regimen=20 (85 mg/m<SUP>2</SUP> =D7 21 days every 28 days) = in=20 patients who had progressed following first-line or second-line = treatment with=20 temozolomide. This dose was selected based on the results of a phase I = trial in=20 patients previously treated with temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR12">12</A></CITE>].=20 </P></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>Patient eligibility</DIV> <P class=3D"">Adult patients (at least 18 years of age) with = histologically=20 confirmed, temozolomide-refractory, WHO grade III or IV glioma and a = Karnofsky=20 Performance Status (KPS) of 60 or higher were included. Patients were = eligible=20 and considered refractory to temozolomide if they developed progressive = disease=20 during temozolomide treatment or less than 3 months after = completing=20 previous temozolomide treatment. </P> <P class=3D"">Adequate laboratory values were required as follows: = absolute=20 neutrophil count ≥1,500/μl, platelet count = ≥100,000/μl, hemoglobin greater than=20 10 g/dl or 100 g/l, blood urea nitrogen and serum creatinine = less than=20 1.5 times the upper limit of laboratory normal, total and direct serum = bilirubin=20 less than 1.5 times the upper limit of laboratory normal, aspartate=20 aminotransferase or alanine aminotransferase less than 3 times the upper = limit=20 of laboratory normal, and alkaline phosphatase less than 2 times the = upper limit=20 of laboratory normal. Patients were required to have been on a = non-increasing=20 corticosteroid dose for ≥72 h before baseline neuroimaging = and study drug=20 administration, and to have a life expectancy greater than = 12 weeks. All=20 patients were required to provide written informed consent. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Study design</DIV> <P class=3D"">This was a multicenter phase II trial conducted by the = GENOM.=20 Institutional review boards at each study center approved the study. The = primary=20 objective was to assess whether an extended temozolomide dosing schedule = can=20 overcome tumor resistance to the drug. Secondary objectives were = response and=20 tolerability. According to the 2-stage model of Simon et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR13">13</A></CITE>],=20 the primary objective was considered not reached if no objective = response was=20 observed in the first 10 patients or if less than 3 responses were = observed=20 among 29 patients in the second stage. Sample size was estimated = according to=20 the Simon 2-stage phase II design (P<SUB>0</SUB> =3D 5% = response rate;=20 P<SUB>1</SUB> =3D 20% response rate) [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR13">13</A></CITE>].=20 To achieve an (α, β) error of (0.05, 0.2), a total of 29 = patients were required,=20 and to achieve an (α, β) error of (0.05, 0.1), a total of 43 = patients were=20 required. </P></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Treatment</DIV> <P class=3D"">After a 4-week clearance period to allow recovery from = toxicities,=20 patients received temozolomide at a starting dose of=20 85 mg/m<SUP>2</SUP>/day in a fasting state for 21 consecutive days = every=20 28-day cycle. Temozolomide treatment was administered until disease = progression=20 (PD) or unacceptable toxicity occurred. Three dose levels were defined:=20 85 mg/m<SUP>2</SUP>, 75 mg/m<SUP>2</SUP>, and=20 65 mg/m<SUP>2</SUP>. If neutrophils were over 1500/μl and = platelets over=20 100,000/μl patients were treated at the 85 mg/m<SUP>2</SUP> = dose;=20 otherwise, treatment was delayed for 1 week to a maximum of = 3 weeks=20 until recovery. If neutrophils were below 500/μl for 5 days, = or platelets=20 were below 25,000/μl, or if the treatment delay was greater than = 2 weeks,=20 the dose was reduced to the next lower level. If nonhematologic toxicity = of=20 grade 3 or greater occurred, the dose was also reduced. Prophylactic = antiemetic=20 therapy with metoclopramide or 5-HT antagonist was administered to all = patients.=20 No <I>Pneumocystis jirovecii</I> pneumonia prophylaxis was administered. = </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Assessment of response and safety</DIV> <P class=3D"">Response was assessed according to Macdonald=92s criteria = [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR14">14</A></CITE>].=20 Neurologic examination and steroid dose modification were recorded at = each=20 cycle. Neuroimaging with gadolinium-enhanced MRI was performed at least = every 2=20 cycles or if PD was suspected based on neurologic symptoms. Complete = response=20 was defined as complete disappearance of all detectable tumors as = determined by=20 2 gadolinium-enhanced MRI scans of the brain performed not less than=20 4 weeks apart. Adverse events were graded according to the National = Cancer=20 Institute Common Terminology Criteria for Adverse Events v3.0. = </P></DIV></DIV> <DIV class=3D""><A name=3DSec7></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3DPara> <DIV class=3D"">A total of 47 patients were enrolled and received at = least 1 cycle=20 of temozolomide. All patients were assessable for response and safety. = Baseline=20 patient characteristics are shown in Table <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Tab1">1</A>.=20 Median time from the diagnosis to study entry was 14 months (range=20 6=96126 months). Before study entry, patients had received a median = of 6=20 (range 1=9621) cycles of temozolomide: 39 patients (83%) as part of = initial=20 therapy and 23 patients (49%) as second-line therapy. Thus, some = patients had=20 received temozolomide as part of both first- and second-line therapy. = All=20 patients had progressed during or within 3 months of completing=20 standard-dose therapy and at least 6 months after completing=20 chemoradiotherapy. No patients received dose-dense temozolomide before = study=20 entry. Anticonvulsant therapy was administered to 31 patients (66%). The = most=20 frequently used anticonvulsants were phenytoin in 17 patients (55%), = valproic=20 acid in 11 patients (36%), gabapentin in 6 patients (19%), and = levetiracetam in=20 5 patients (16%). Some patients received more than 1 anticonvulsant = drug.<A=20 name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Patient = demographics=20 and baseline clinical characteristics (<I>N</I> =3D 47) </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dleft></COLGROUP> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Mean age, years (range)</P></TD> <TD align=3Dleft> <P class=3D"">50 (20=9677)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Sex, <I>n</I> (%) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Male</P></TD> <TD align=3Dleft> <P class=3D"">33 (70)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Female</P></TD> <TD align=3Dleft> <P class=3D"">14 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">ECOG performance status, <I>n</I> (%) </P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 0</P></TD> <TD align=3Dleft> <P class=3D"">8 (17)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 1</P></TD> <TD align=3Dleft> <P class=3D"">20 (43)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 2</P></TD> <TD align=3Dleft> <P class=3D"">19 (40)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Tumor histology, <I>n</I> (%) </P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Glioblastoma</P></TD> <TD align=3Dleft> <P class=3D"">27 (57)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Anaplastic = astrocytoma</P></TD> <TD align=3Dleft> <P class=3D"">15 (32)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Anaplastic = oligodendroglioma</P></TD> <TD align=3Dleft> <P class=3D"">3 (6)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Other</P></TD> <TD align=3Dleft> <P class=3D"">2 (4)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Prior surgery, <I>n</I> (%) </P></TD> <TD align=3Dleft> </TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Biopsy only</P></TD> <TD align=3Dleft> <P class=3D"">9 (19)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Partial resection</P></TD> <TD align=3Dleft> <P class=3D"">20 (43)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Gross total = resection</P></TD> <TD align=3Dleft> <P class=3D"">17 (36)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Biopsy and partial = resection</P></TD> <TD align=3Dleft> <P class=3D"">1 (2)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Prior first-line chemotherapy, <I>n</I> (%) = </P></TD> <TD align=3Dleft> <P class=3D""><I>n</I> =3D 47 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Temozolomide</P></TD> <TD align=3Dleft> <P class=3D"">38 (81)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Carmustine</P></TD> <TD align=3Dleft> <P class=3D"">4 (9)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> PCV</P></TD> <TD align=3Dleft> <P class=3D"">4 (9)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P=20 = class=3D""> Temozolomide + cisplatin</P>= </TD> <TD align=3Dleft> <P class=3D"">1 (2)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Prior second-line chemotherapy, <I>n</I> (%) = </P></TD> <TD align=3Dleft> <P class=3D""><I>n</I> =3D 23 </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Temozolomide = monotherapy</P></TD> <TD align=3Dleft> <P class=3D"">21</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Temozolomide-based=20 polychemotherapy</P></TD> <TD align=3Dleft> <P class=3D"">2</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>ECOG</I> Eastern Cooperative Oncology Group; = <I>PCV</I>=20 procarbazine, lomustine, and vincristine </DIV></DIV></DIV></DIV></DIV> <P class=3D"">Patients received a median of 2 (range, 1=9613) cycles of = temozolomide=20 on study, and a total of 168 treatment cycles were administered. Sixteen = cycles=20 were delayed in 7 patients as a result of hematologic toxicity in 3 = patients,=20 nonhematologic toxicity in 2 patients, and for administrative reasons in = 2=20 patients. Only 3 cycles were dose reduced in 2 patients because of = hematologic=20 toxicity. </P> <P class=3D"">Among 47 treated patients, 3 (6.4%) had a partial response = (95%=20 confidence interval [CI]: 0.6%, 13.2%), including 1 patient with=20 oligodendroglioma who had received 3 previous lines of therapy, 1 = patient with a=20 glioblastoma who had received 2 previous lines of therapy, and 1 patient = with a=20 glioblastoma who had received 1 previous line of therapy. Duration of = the=20 responses was 8, 3.2, and 3.5 months, respectively. In addition, 15 = patients (31.9%) had stable disease (SD). Median duration of SD was=20 2.1 months, and 2 patients remained stable for greater than = 6 months=20 (14 and 16 months). One of 3 responders, 6 of 15 patients with SD, = and 9 of=20 30 patients with PD on study had a response or SD lasting greater than=20 6 months during previous temozolomide therapy. All 3 patients who = had a=20 response or SD lasting greater than 6 months on study also had a = response=20 or SD lasting greater than 6 months during previous temozolomide = therapy.=20 </P> <DIV class=3DPara> <DIV class=3D"">At a median follow up of 3.6 months, median time to = progression was 2 months (95% CI: 1.6, 2.4 months; = Fig. <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Fig1">1</A>)=20 and median overall survival from study entry was 5.1 months (95% = CI: 3.7,=20 6.5 months; Fig. <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Fig2">2</A>).=20 The 6-month progression-free survival (PFS) rates were 16.7% for the = overall=20 population, 0% among patients with glioblastoma, and 37.5% among = patients with=20 anaplastic astrocytoma or oligodendroglioma. The 6-month overall = survival rate=20 was 41.6% (95% CI: 25.1%, 58.1%).=20 <DIV class=3DFigure><A name=3DFig1></A><IMG=20 alt=3DMediaObjects/11060_2009_9980_Fig1_HTML.gif=20 src=3D"http://www.springerlink.com/content/p11524720808612w/MediaObjects/= 11060_2009_9980_Fig1_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 1 </SPAN>Kaplan=96Meier estimate=20 of time to progression </DIV> <HR> <DIV class=3DFigure><A name=3DFig2></A><IMG=20 alt=3DMediaObjects/11060_2009_9980_Fig2_HTML.gif=20 src=3D"http://www.springerlink.com/content/p11524720808612w/MediaObjects/= 11060_2009_9980_Fig2_HTML.gif"></DIV> <DIV class=3DCapt><SPAN = class=3DCaptNr>Fig. 2 </SPAN>Kaplan=96Meier estimate=20 of overall survival </DIV> <HR> </DIV></DIV> <DIV class=3DPara> <DIV class=3D"">The most common hematologic toxicities were lymphopenia, = thrombocytopenia, and leukopenia (Table <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Tab2">2</A>).=20 Lymphopenia occurred in 83% of patients and was grade 3 in 28%, but no=20 opportunistic infections occurred. The most common nonhematologic = adverse events=20 or laboratory abnormalities were nausea/vomiting, asthenia, and mild=20 asymptomatic transaminitis (Table <A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#Tab3">3</A>).=20 Most nonhematologic adverse events and laboratory abnormalities were = mild to=20 moderate in severity, and there was no grade 4 toxicity.<A = name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Hematologic toxicity=20 by grade </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft rowSpan=3D2> </TH> <TH align=3Dleft colSpan=3D3 char=3D"("> <P class=3D"">Patients, <I>n</I> (%) </P></TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 1 or 2</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 3</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Total</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lymphopenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">26 (55)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">13 (28)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">39 (83)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Thrombocytopenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">5 (11)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">14 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Leukopenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">13 (28)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">14 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Anemia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">7 (15)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Neutropenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (17)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD></TR></TBODY></TABLE><A = name=3DTab3></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 3 </SPAN>Most = common=20 nonhematologic adverse events and laboratory abnormalities by grade = </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft rowSpan=3D2> </TH> <TH align=3Dleft colSpan=3D3 char=3D"("> <P class=3D"">Patients, <I>n</I> (%) </P></TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 1 or 2</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Grade 3</P></TH> <TH align=3Dleft char=3D"("> <P class=3D"">Total</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D4> <P class=3D"">Adverse events</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Nausea/vomiting</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">12 (26)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">13 (28)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Asthenia</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (17)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (17)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Diarrhea</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">5 (11)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">5 (11)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Constipation</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Mucositis</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">2 (4)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">3 (6)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D4> <P class=3D"">Laboratory abnormalities</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GPT</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">24 (51)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">24 (51)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GOT</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (19)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Creatinine</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">6 (13)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">6 (13)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> GGT</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Bilirubin</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">=96</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">1 (2</P></TD></TR></TBODY></TABLE> <DIV class=3DCapt> <DIV class=3DCaptCont> <DIV class=3D""><I>GPT</I> glutamic-pyruvic transaminase, <I>GOT</I>=20 glutamic-oxaloacetic transaminase, <I>GGT</I> gamma-glutamyl transferase = </DIV></DIV></DIV></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec8></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">Since the publication of the pivotal phase III trial in = 2005=20 demonstrating the superiority of combining radiotherapy with = temozolomide=20 compared with radiotherapy alone in newly diagnosed glioblastoma = patients=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR8">8</A></CITE>],=20 temozolomide has become the standard of care for initial treatment of=20 glioblastoma and is widely used for treatment of anaplastic glioma.=20 Consequently, standard-dose temozolomide may no longer be the best = treatment=20 option at recurrence. A variety of options have been explored, including = retreatment with temozolomide using a dose-dense schedule or treatment = with=20 nitrosoureas, irinotecan, bevacizumab, or a variety of novel = combinations of=20 these and other agents [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR15">15</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR19">19</A></CITE>].=20 Carmustine has demonstrated only limited activity after temozolomide = [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR18">18</A></CITE>],=20 whereas irinotecan, in combination with bevacizumab, carmustine, or = thalidomide,=20 has demonstrated promising activity in this setting [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR15">15</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR19">19</A></CITE>].=20 Presumably most high-grade gliomas are refractory to alkylating agents = at=20 recurrence following initial treatment with temozolomide. However, a = recent=20 report by Perry et al. [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR20">20</A></CITE>]=20 of interim data from the RESCUE study has shown that retreatment with = continuous=20 low-dose daily temozolomide resulted in favorable 6-month PFS rates in = patients=20 who progressed during or after first-line temozolomide. Other studies = have also=20 demonstrated the activity of dose-dense temozolomide regimens in this = setting=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR21">21</A></CITE>].=20 </P> <P class=3D"">The results of the present study have further demonstrated = that=20 retreatment with temozolomide using an extended, dose-dense schedule can = result=20 in objective responses in patients previously exposed to temozolomide as = part of=20 their initial treatment. Although the observed 6.3% partial response = rate and=20 6-month PFS rate were modest, patients enrolled in this study were = pretreated=20 with a median of 6 cycles of temozolomide, and many patients received = extended=20 treatment with up to 21 cycles of standard-dose temozolomide before = study entry.=20 Similarly, among patients enrolled in the RESCUE study, those who = received=20 prolonged maintenance therapy with standard-dose temozolomide (beyond 6 = cycles)=20 had a low 6-month PFS rate (9.5%) [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR20">20</A></CITE>].=20 In addition, all patients entered the present study at least = 6 months after=20 completing previous radiotherapy. This suggests that the responses = observed in=20 the present study were not an artifact of pseudoprogression, but this = cannot be=20 completely ruled out. </P> <P class=3D"">It has been observed that patients who have prolonged SD = after=20 primary temozolomide treatment often have a prolonged response to = retreatment=20 with temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR22">22</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>].=20 Consistent with these published reports, all patients who had a durable = response=20 or SD in the present study had previously had a durable response or SD = to first-=20 or second-line temozolomide. It should be noted, however, that objective = responses and SD have been observed in patients who had a short duration = of=20 response to first-line temozolomide. Therefore, no patient should be = excluded=20 from retreatment with an extended temozolomide regimen based on the = quality of=20 their response to first-line temozolomide. </P> <P class=3D"">Compared with the standard 5-day dosing schedule every = 28-day cycle,=20 the extended dose-dense schedules result in approximately a 2-fold = greater=20 exposure to temozolomide and may have greater potential to deplete MGMT = activity=20 within tumor cells and overcome resistance [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR11">11</A></CITE>].=20 The first report of an extended temozolomide regimen investigated a dose = of=20 75 mg/m<SUP>2</SUP>/day for 6 or 7 consecutive weeks [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR24">24</A></CITE>].=20 This schedule resulted in a 41% response rate among 17 patients with = recurrent=20 glioma. Subsequent studies in glioblastoma investigating 2 different = extended=20 temozolomide schedules (7 consecutive days every 2 weeks, or 21 = consecutive=20 days every 28 days) showed that both schedules resulted in a = significant=20 and prolonged depletion of MGMT in peripheral blood mononuclear cells, = which led=20 to the hypothesis that these dose-dense regimens could potentially = enhance=20 antitumor activity [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR10">10</A></CITE>].=20 Two phase II trials in patients with recurrent glioblastoma also = demonstrated=20 that these regimens are highly active [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR25">25</A></CITE>].=20 In the first study conducted in temozolomide-naive patients, the 21-day=20 continuous schedule resulted in a 9% response rate and a 6-month PFS = rate of 30%=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR25">25</A></CITE>].=20 In the second study, the majority of patients had not been previously = exposed to=20 temozolomide, and the alternating weekly regimen resulted in a response = rate of=20 15% and a 6-month PFS rate of 44% [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>].=20 Therefore, the fact that 2 of 27 (7%) glioblastoma patients in the = present study=20 who were previously treated with temozolomide had an objective response = supports=20 the hypothesis that this dose-dense regimen may overcome resistance. One = limitation of the present study is the lack of data on MGMT methylation = status=20 of these tumors. However, MGMT methylation status at initial diagnosis = has=20 limited value in the recurrent setting, particularly given the = observation that=20 methylation patterns within the tumor can change from initial diagnosis = to=20 recurrence. </P> <P class=3D"">Toxicity associated with extended, dose-dense temozolomide = schedules=20 has been reported to be greater than that associated with the = conventional 5-day=20 schedule and to consist mainly of lymphopenia [<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR23">23</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR25">25</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/p11524720808612w/fulltext.htm= l#CR28">28</A></CITE>].=20 In the present study, grade 3 or higher lymphopenia occurred in nearly = 30% of=20 patients. However, no complications related to immunodeficiency such as=20 <I>Pneumocystis jirovecii</I> pneumonia were reported, even in the = absence of=20 PCP prophylaxis. All toxicities were manageable, and few patients = required=20 treatment delays or dose reductions. </P> <P class=3D"">In conclusion, this extended dose-dense schedule of = temozolomide=20 appears to have activity, albeit modest, in patients who have failed = previous=20 treatment with temozolomide and is associated with manageable toxicity. = These=20 results suggest that extended schedules of temozolomide may be = preferable to the=20 standard temozolomide regimen and should be further evaluated in larger=20 randomized studies with prospective stratification of patients by = primary tumor=20 type and extent of prior temozolomide therapy. The full results of the = RESCUE=20 study are eagerly awaited and may provide further insight regarding how = best to=20 use temozolomide in the recurrent setting. </P></DIV> <DIV class=3DAcknowledgments><SPAN=20 class=3DAcknowledgmentsHeading>Acknowledgments </SPAN><SPAN=20 class=3D"">Financial support for medical editorial assistance was = provided by=20 Schering-Plough International. We thank Jeffrey Riegel, PhD, ProEd=20 Communications, Inc.<SUP>=AE</SUP>, for his medical editorial assistance = with this=20 manuscript.</SPAN> <DIV class=3DFormalPara> <DIV class=3D""><SPAN style=3D"FONT-STYLE: italic; TEXT-DECORATION: = none">Open=20 Access</SPAN> This article is distributed under the terms of = the=20 Creative Commons Attribution Noncommercial License which permits any=20 noncommercial use, distribution, and reproduction in any medium, = provided the=20 original author(s) and source are credited. </DIV></DIV></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>Gilbert MR (2006) Advances in the treatment of = primary=20 brain tumors: dawn of a new era? 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