10.1007/s11060-009-0067-2</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 6.00.6000.16945" 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. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0067-2</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Phase II trial of erlotinib = with=20 temozolomide and radiation in patients with newly diagnosed glioblastoma = multiforme </DIV> <P class=3DAuthorGroup>David M. Peereboom<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/l467p704762u5541/contact.gif" = border=3D0></A></SUP>, Dale R. Shepard<SUP>2</SUP>,=20 Manmeet S. Ahluwalia<SUP>1</SUP>,=20 Cathy J. Brewer<SUP>1</SUP>, Neeraj Agarwal<SUP>1</SUP>,=20 Glen H. J. Stevens<SUP>1</SUP>, = John H. Suh<SUP>1,=20 3</SUP>, Steven A. Toms<SUP>4</SUP>,=20 Michael A. Vogelbaum<SUP>1</SUP>,=20 Robert J. Weil<SUP>1</SUP>, Paul Elson<SUP>5</SUP> and=20 Gene H. Barnett<SUP>1</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Brain Tumor and Neuro-Oncology Center, = Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, = Cleveland,=20 OH 44195, USA</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>Solid Tumor Oncology, Cleveland = Clinic, 9500=20 Euclid Ave, Cleveland, OH 44195, = USA</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>Radiation Oncology, Cleveland Clinic, = 9500=20 Euclid Ave, Cleveland, OH 44195, = USA</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>Neurosurgery, Geisinger Health System, = Danville, PA, USA</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>Quantitative Health Services, = Cleveland=20 Clinic, 9500 Euclid Ave, Cleveland, OH, = USA</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/l467p704762u5541/contact.gif" = border=3D0></TD> = <TD><STRONG>David </STRONG><STRONG>M. </STRONG><STRONG>Peereboo= m</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 href=3D"mailto:peerebd@ccf.org">peerebd@ccf.org</A></TD></TR></TBODY></TA= BLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>23 July 2009 <STRONG>Accepted:=20 </STRONG>9 November 2009 <STRONG>Published online:=20 </STRONG>4 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>Approximately = 40=9650% of=20 glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). = Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active = against=20 refractory GBM. Patients with non-small cell lung cancer and = ≥grade 2=20 erlotinib-induced rash have improved survival. This phase 2 study = assessed the=20 efficacy and safety of concurrent radiation therapy (RT) and = temozolomide with=20 pharmacodynamic dose escalation of erlotinib in patients with newly = diagnosed=20 GBM. Patients received RT 60 Gy in 30 fractions with concurrent=20 temozolomide 75 mg/m<SUP>2</SUP>/day =D7 42 days, = followed in=20 four weeks by temozolomide = 150=96200 mg/m<SUP>2</SUP>/day =D7 5,=20 every 28 days for 12 cycles. Patients received erlotinib, = 50 mg/day=20 and increased by 50 mg/day every 2 weeks until the occurrence = of grade=20 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease = progression. Twenty-seven patients were treated in this study. = Twenty-two (81%)=20 patients came off study for progressive disease (18 [67%]) or adverse = events (4=20 [15%]). Eighteen patients (67%) have died. Median progression-free = survival was=20 2.8 months, and the median overall survival was 8.6 months. = Five=20 patients remain on study with a median follow-up of 16 months. = Grade 3/4=20 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and = febrile=20 neutropenia. There were four deaths on study, three definitely=20 treatment-related; therefore, the trial was terminated after accrual of = 27 of 30=20 planned patients. Erlotinib co administered with RT and temozolomide was = not=20 efficacious and had an unacceptable toxicity. </DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>EGFR=20 inhibitor - Temozolomide - Erlotinib - Glio= blastoma=20 multiforme - Newly=20 diagnosed - Chemotherapy - Efficacy - Phase= II=20 </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">Glioblastoma multiforme (GBM) is an aggressive primary = tumor of the=20 central nervous system accounting for about 50% of all adult gliomas = [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR1">1</A></CITE>].=20 Based on a significant survival advantage provided by the use of = concurrent=20 chemo-radiotherapy and adjuvant chemotherapy with temozolomide = demonstrated in a=20 recent phase III trial, this regimen is now considered to be standard of = care=20 for newly diagnosed GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>].=20 Despite an improvement in overall survival (OS) with this regimen, the = prognosis=20 of patients with GBM remains poor with a median OS of 9 to = 15 months and a=20 2-year survival rate of 9=9626% [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR3">3</A></CITE>].=20 </P> <P class=3D"">Approximately 40=9650% of GBM overexpress epidermal growth = factor=20 receptor (EGFR), a type I receptor tyrosine kinase correlated with an = aggressive=20 phenotype [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR4">4</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR6">6</A></CITE>].=20 EGFR activates an intracellular tyrosine kinase that leads to a signal=20 transduction cascade that enhances survival and infiltration of GBM = cells in=20 vitro [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR8">8</A></CITE>].=20 Overexpression of EGFR correlates with increased cellular proliferation, = tumorigenesis, decreased apoptosis, and a poor prognosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR9">9</A></CITE>].=20 In addition, EGFR overexpression in GBM correlates with radioresistance=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR11">11</A></CITE>].=20 </P> <P class=3D"">Erlotinib (Tarceva=99) is a specific, potent inhibitor of = EGFR=20 tyrosine kinase with antitumor activity in lung and pancreatic cancer = [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR13">13</A></CITE>].=20 In preclinical studies in GBM cell lines, erlotinib suppressed=20 anchorage-independent growth, had antiproliferative and apoptotic = effects, and=20 had activity against cell lines that harbor the EGFRvIII mutant receptor = [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR15">15</A></CITE>].=20 Erlotinib alone or with temozolomide has antitumor activity in phase I = or II=20 studies with patients with stable or refractory GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR17">17</A></CITE>].=20 Erlotinib was well tolerated in phase I trials of patients with solid=20 malignancies, including newly diagnosed GBM; grade 3 rash, fatigue, = diarrhea, or=20 stomatitis occurred in 5=9615% of patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR18">18</A></CITE>].=20 </P> <P class=3D"">In this study, we investigated the efficacy and safety of = erlotinib=20 in combination with the standard regimen of temozolomide and = radiotherapy (RT)=20 in patients with newly diagnosed GBM. In studies of erlotinib in = patients with=20 non-small cell lung cancer, survival correlated with development of = grade 2 skin=20 rash, suggesting a physiologic marker for maximal dose [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR19">19</A></CITE>].=20 The primary objective of this trial was to determine progression free = survival=20 (PFS) and OS. Toxicity and the feasibility of pharmacodynamic dose = escalation=20 were secondary objectives. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Patients</DIV> <P class=3D"">Patients with histologically-proven, newly diagnosed GBM = who were=20 within 28 days of their diagnostic biopsy or resection, were at = least=20 18 years old, and with a Karnofsky performance score of at least 60 = were=20 eligible for this IRB-approved study. Prior administration of = temozolomide,=20 tyrosine kinase inhibitors, or cranial radiation, or concurrent = administration=20 of hepatic cytochrome P-450 enzyme-inducing antiepileptic drugs (EIAEDs) = such as=20 phenytoin, carbamazepine, phenobarbital, felbamate, oxycarbazepine, or=20 topiramate were not allowed. Patients on EIAEDs were transitioned to=20 levetiracetam prior to starting the trial. An absolute neutrophil=20 count >1.5 =D7 10<SUP>9</SUP> per liter, a platelet = count=20 >100 =D7 10<SUP>9</SUP> per liter; hemoglobin = >90 g/l, serum=20 creatinine and total serum bilirubin <1.5 times the upper limit of = normal,=20 aspartate aminotransferase or alanine aminotransferase <2.5 times the = upper=20 limit of normal, and alkaline phosphatase <2.5 times the upper limit = of=20 normal were required. Patients of reproductive potential were required = to use=20 effective contraception. Written informed consent was required prior to=20 treatment. </P> <P class=3D"">Patients with a severe underlying disease, including human = immunodeficiency virus or chronic hepatitis B or C infection were = excluded.=20 Other antineoplastic therapy during study drug administration was = prohibited.=20 Women who were pregnant or breast feeding were excluded. Patients with = any=20 malignancy within 3 years with the exception of surgically cured=20 carcinoma-in situ of the cervix, non-melanoma skin cancer, or adequately = treated=20 stage I or II cancer in complete remission were excluded. Demonstration = of EGFR=20 expression by the tumor or presence of measurable disease on = neuroimaging was=20 not required for enrollment in the trial. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Study design</DIV> <P class=3D"">All patients were treated at the Cleveland Clinic. RT was=20 administered in 2 Gy/day fractions, 5 days per week, to a = total of=20 60 Gy over six weeks. The target volume for the initial and = cone-down=20 volume was based on the post-operative MRI. The initial target volume = included=20 the edema on T2 sequences plus a 2.0-cm margin; if no edema was present, = a=20 2.5 cm margin beyond the contrast-enhanced lesion and resection = cavity was=20 treated. The initial target volume was treated with 46 Gy in 23 = fractions.=20 The cone-down tumor volume included the resection cavity with = contrast-enhancing=20 lesion plus a 2.5-cm margin. </P> <P class=3D"">Temozolomide administration began on day 1 of RT at=20 75 mg/m<SUP>2</SUP>/day and continued for 42 days. = Temozolomide was=20 taken while fasting, 1 h before RT, and in the morning on days = without RT.=20 All patients received a single inhaled dose of pentamidine for = prophylaxis=20 against pneumocystis pneumonia during weeks 1 and 4 of RT. The initial = dose of=20 erlotinib was 50 mg/day, beginning on Day 1 of RT, with escalation = by=20 50 mg/day every 2 weeks until the occurrence of an = erlotinib-induced=20 grade 2 or greater rash outside the radiation field or a maximum dose of = 150 mg/day. Erlotinib was continued until disease progression. = Patients who=20 developed seizures were treated with non-EIAEDs. Grade 2 or higher skin = rash was=20 treated with minocycline, topical tetracycline, topical retinoids or = oral=20 antibacterial agents. </P> <P class=3D"">An MRI was obtained four weeks after completion of RT as a = baseline.=20 Patients received temozolomide daily for 5 days during every = 28 day=20 cycle for up to 12 cycles. Patients received temozolomide=20 150 mg/m<SUP>2</SUP>/day for 5 days for cycle 1. In the = absence of=20 grade 3 or 4 neutropenia or thrombocytopenia during cycle 1, patients = received=20 temozolomide 200 mg/m<SUP>2</SUP>/day for 5 days for 11 = additional=20 cycles. CBCs were monitored weekly during weeks 3=966 of radiation = therapy and=20 subsequently on day 1 of each post-radiation cycle of therapy. = Compliance with=20 this schedule of monitoring was estimated to be at least 95%. </P> <P class=3D"">Hematopoietic growth factors were only used in patients = with=20 persistent refractory neutropenia. Prophylactic antiemetics were used = during RT=20 at the discretion of the investigator. Anticonvulsants and = corticosteroids were=20 administered as needed with EIAEDs avoided if possible. Patients who=20 inadvertently received EIAEDs during the study transitioned to = non-EIAEDs as=20 soon as feasible. </P></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Dose reductions</DIV> <P class=3D"">During RT, temozolomide was held and not restarted for an=20 ANC<1500/μl or platelets <100,000/μl. There was no dose = reduction for=20 temozolomide during RT. During post-RT temozolomide, the cycle was = initiated=20 once ANC <U>></U>1500 and platelets <U>></U>100,000. In = patients=20 with grade 3 temozolomide-related toxicity, temozolomide was held until = the=20 toxicity returned to grade 0=961. If the ANC nadir from the previous = cycle=20 was <500 and/or platelet nadir was <20,000, the = temozolomide=20 dose was decreased by 25% for the subsequent cycle. For reversible, = grade 4=20 non-hematological temozolomide-related toxicity, the temozolomide dose = was=20 reduced to 80% of the dose for the previous cycle for all subsequent = cycles. If=20 temozolomide-related toxicity did not resolve within 2 weeks or if = the=20 toxicity was not tolerated, temozolomide was discontinued, but any = remaining RT=20 and erlotinib was given. </P> <P class=3D"">Erlotinib was held for grade <U>></U>3 rash until=20 improvement to grade ≤2 and resumed with a 50 mg/day dose = reduction. If=20 erlotinib-related toxicity did not resolve within 2 weeks or the = toxicity=20 was intolerable, erlotinib was discontinued but any remaining RT and=20 temozolomide was given. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Assessment of response and safety</DIV> <P class=3D"">Patients were removed from the study for unacceptable = toxicity or=20 toxicity leading to discontinuation of both temozolomide and erlotinib. = Other=20 criteria for study discontinuation were patient choice, noncompliance, = serious=20 concurrent illness, or progressive disease. Progressive disease was = defined as=20 <U>></U>25% increase in the sum of the products of all T1 weighted=20 gadolinium-enhancing measurable disease compared with the baseline = measurement,=20 or the appearance of new lesions. A PET scan, blood volume MRI or tissue = biopsy=20 were attempted, if necessary, to distinguish tumor growth from=20 pseudo-progression. Cases of possible progression were also reviewed as=20 necessary at a multidisciplinary brain tumor conference. </P> <P class=3D"">Physical examinations, assessment of routine labs, and = evaluation of=20 toxicity were conducted prior to the study and at scheduled intervals = throughout=20 the study. A gadolinium-enhanced MRI of brain was performed within = 3 weeks=20 before starting radiation and before cycles 1, 3, 5, 7, 9, and 11 of = post=20 radiation temozolomide. An MRI was obtained every 2 months during = the first=20 year after completion of temozolomide and every 3 months = thereafter.=20 </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Statistical methods</DIV> <P class=3D"">The primary endpoints of the study were PFS and OS. = Assuming a=20 6-month PFS of 50%, based on historical controls, it was estimated that = 30=20 patients would need to be assessed and followed for at least six months = in order=20 to have 80% power, based on a 2-sided <I>P</I> =3D .05 exact = binomial=20 test, to detect an increase in PFS to 75% [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR22">22</A></CITE>].=20 </P> <P class=3D"">With 30 patients, the incidence of specific toxicities, = and key=20 quantiles such as 6-month and 1-year PFS and OS could be estimated using = 95%=20 confidence intervals with maximum half-widths of 19%. PFS and OS were = calculated=20 from the date of study entry to the date of disease progression, death, = or final=20 follow-up and were summarized using the method of Kaplan and Meier. If = the=20 underlying incidence for a specific toxicity was <U><</U>5%, there = was=20 a <U>></U>79% chance of observing the toxicity in at least one = of the 30=20 patients enrolled in the study. Statistical significance was defined as=20 <I>P</I> < 0.05 and statistical tests were two-sided. All = analyses=20 were conducted using SAS<SUP>=AE</SUP> version 8.0 software (SAS = Institute, Inc.,=20 Cary, NC). </P></DIV> <DIV class=3D""><A name=3DSec8></A> <DIV class=3DHeading3>Methyl guanine methyl transferase (MGMT) promoter=20 methylation analysis</DIV> <P class=3D"">Nested polymerase chain reaction (PCR) was used for = amplification of=20 bisulfite treated genomic DNA. First round PCR MGMT primers: forward is=20 TTTTTTTGTTTTTTTTAGGTTTT and reverse is AACCTAAAACTAACACCTAAAAA. The = annealing=20 temperature was 45=B0C. The second round PCR MGMT primers: forward is=20 CCTAATGTTGGGATAGTT, reverse is CAACATCACTAACACCTAACC, and the annealing=20 temperature was 60=B0C. Second reverse primer sequences are derived from = Parkinson=20 et al. and from the NCBI sequence site; primer sequences are available = on=20 request [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR23">23</A></CITE>].=20 Platinum <I>Taq</I>DNA Polymerase (Invitrogen, California, USA) was used = according to the manufacturer=92s instructions. PCR amplicons were = purified using=20 QIAquick PCR Purification Kit PCR (QIAGEN Inc. Valencia, California, = USA).=20 Sequencing was performed in forward and reverse directions using the = same=20 primers as those used for the second round PCR, according to standard=20 techniques. Colon cancer line SW48, in which all 28 promoter sites are=20 methylated was used as a positive control. </P></DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Patient characteristics</DIV> <DIV class=3DPara> <DIV class=3D"">Twenty-eight patients were enrolled between December = 2003 and=20 December 2005. One patient did not receive treatment and was excluded = from all=20 efficacy and safety analyses. Among the 27 evaluable patients, the = median age=20 was 52 years and the median Karnofsky performance status (KPS) was = 90=20 (Table <A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#Tab1">1</A>).=20 Eight patients had gross total resection, eight had subtotal resection, = and 11=20 had biopsy only. RPA grouping was as follows: group III=9611 patients; = group IV=967;=20 and group V=969 [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR24">24</A></CITE>].=20 EGFR was amplified in 9 patients, not amplified in 17 patients, and not=20 determined in 1 patient.<A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Patient = demographics=20 </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Characteristic</P></TH> <TH align=3Dleft char=3D"("> </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Age, years (median, range)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">52 (18=9674)</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""> Men</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">17 (63)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Women</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">10 (37)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Karnofsky performance status (<I>n</I>, %) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 90=96100</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">18 (67)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 60=9680</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (33)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Extent of surgery (<I>n</I>, %) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Gross total resection</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Subtotal resection</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Biopsy only</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">11 (40)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">EGFR status (<I>n</I> =3D 26) (<I>n</I>, = %) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Amplified</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (35)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Negative</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">17 = (65)</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Efficacy</DIV> <P class=3D"">Twenty of the 27 patients (74%) completed the first = 42 day=20 treatment period during which chemotherapy was given concurrently with=20 radiation, with no dose modifications. Three patients had treatment = delayed, and=20 four patients discontinued treatment with erlotinib and/or temozolomide = due to=20 toxicity. Thirteen patients (48%) continued on treatment post radiation = and=20 received a median of five cycles of therapy (range 1=9618+). </P> <P class=3D"">Twenty-two (81%) patients had progressive disease and 4 = (15%)=20 patients came off study for adverse events. Eighteen patients (67%) have = died.=20 The 6-month progression free survival was 30%, and the median = progression-free=20 survival was 2.8 months. The median overall survival was = 8.6 months.=20 Five patients remain on study with a median follow-up of 16 months = (range=20 9.7=9621.5 months). </P> <P class=3D"">There was a trend but no statistical correlation between = efficacy=20 and EGFR amplification. The overall survival of those with and without = EGFR=20 amplification was 11 months and 8 months, respectively=20 (<I>P</I> =3D 0.13). The failure free survival of those with = and without=20 EGFR amplification was 5.9 months and 2.6 months, respectively = (<I>P</I> =3D 0.16). </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Toxicity</DIV> <DIV class=3DPara> <DIV class=3D"">The maximum dose of erlotinib reached before the = occurrence of=20 grade 2 rash was 50 mg/day in one patient, 100 mg/day in five=20 patients, and 150 mg/day in 21 patients. Four deaths occurred = during the=20 study, three of which were definitely related to treatment. Three deaths = occurred in the last four patients accrued to the trial with termination = of the=20 trial after enrolling 27 of the 30 planned patients. One patient died of = pneumocystis carinii pneumonia (PCP), confirmed by bronchoscopy, despite = prophylaxis with pentamidine. Two patients died of refractory bone = marrow=20 aplasia and one died of non-neutropenic sepsis. Treatment-related Grade = 3 or 4=20 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and = febrile=20 neutropenia (Table <A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#Tab2">2</A>).<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Treatment-related=20 adverse events </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <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> <P class=3D"">Adverse event (27 patients)</P></TH> <TH align=3Dleft colSpan=3D4 char=3D"."> <P class=3D"">Grade (n)</P></TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"."> <P class=3D"">1=962</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">3</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">4</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">5</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Neutropenia with fever</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sepsis without neutropenia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Pneumocystis pneumonia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Neutropenia without fever</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Thrombocytopenia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lymphopenia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">15</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Anemia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">6</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">ALT increase</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">10</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Fatigue</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">23</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>MGMT promoter methylation analysis</DIV> <P class=3D"">Adequate paraffin-embedded tissue was available for 10 = patients.=20 After appropriate processing and digestion, suitable genomic DNA for = analysis=20 was obtained in four patients. Each of the four patients in whom = adequate DNA=20 was available for bisulfite methylation analysis showed methylation of = at least=20 one of 28 potential <I>MGMT</I> promoter sites (range, 1=9617 sites = methylated;=20 average of seven sites; median value five sites). </P></DIV></DIV> <DIV class=3D""><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">The goal of this study was to estimate the PFS and OS in = patients=20 with newly diagnosed GBM treated with erlotinib and RT-temozolomide. The = primary=20 objective of 6-month PFS of 75% was not met. In this study the 6-month = PFS was=20 30%, the median PFS was 2.8 months, and the median OS was = 8.6 months.=20 These results are substantially worse than the median PFS of = 6.9 months and=20 the OS of 14.6 months for patients who receive RT with concurrent=20 temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>].=20 The short PFS might raise the question as to whether patients were taken = off=20 study prematurely for pseudo-progression [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR25">25</A></CITE>].=20 Cases in question were reviewed by a multidisciplinary brain tumor = board. At=20 least one patient had a biopsy performed which confirmed progression. = The short=20 overall survival of patients in this study also speaks against=20 pseudo-progression as a significant event for patients in this trial. = </P> <P class=3D"">Although inhibition of EGFR with receptor tyrosine kinase=20 inhibitors, such as erlotinib or gefitinib showed promise when this = study was=20 designed, these agents have subsequently shown only moderate activity as = single=20 agents in patients with GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR26">26</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR29">29</A></CITE>].=20 In one trial, 10 of 24 (42%) patients with recurrent or progressive GBM=20 receiving erlotinib had a partial response or stable disease with a = median time=20 to progression of about 4.5 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR17">17</A></CITE>].=20 Analogous results were observed with EGFR antagonists in patients with = non-small=20 cell lung cancer in that second and third line therapy with single agent = gefitinib or erlotinib produced survival benefits while these agents = combined=20 with standard cytotoxic regimens as first-line therapy for metastatic = disease=20 showed no benefit [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR30">30</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR32">32</A></CITE>].=20 </P> <P class=3D"">There are several proposed mechanisms for the poor = efficacy of=20 single agent erlotinib and the antagonism of erlotinib in combination = with=20 chemotherapy. Although activation of EGFR is important for the = activation of=20 phosphatidylinositol 3-kinase (PI3K) and Akt, numerous receptor kinases = may be=20 activated by GBM cells and treatment with a single tyrosine kinase = inhibitor,=20 such as erlotinib, is not sufficient to decrease cell signaling and=20 anchorage-independent growth [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR33">33</A></CITE>].=20 One potential mechanism for antagonism is that EGFR inhibitors, such as=20 erlotinib, may cause cell cycle arrest thereby making cells less = sensitive to=20 the cell cycle dependent effects of radiation therapy and temozolomide. = In vitro=20 and preclinical studies have shown schedule dependent interactions = between the=20 EGFR inhibitors and chemotherapy. The tyrosine kinase inhibitor = gefitinib=20 significantly improved the antitumor activity of paclitaxel in a human = mammary=20 carcinoma xenograft model, but only when gefitinib was given on a = pulsatile=20 schedule, not with continuous dosing [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR34">34</A></CITE>].=20 Similarly, the cytotoxicity of erlotinib with pemetrexed in NSCLC cells = was=20 synergistic when administered together or with pemetrexed followed by = erlotinib,=20 however there was antagonistic activity when erlotinib was administered = prior to=20 pemetrexed in erlotinib-sensitive cells [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR35">35</A></CITE>].=20 The combination of erlotinib and bortezomib had additive cytotoxicity in = the=20 H358 bronchioalveolar cell line, but there was schedule dependence with = the=20 additive effect only when the two agents were used together or = bortezomib was=20 added first [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR36">36</A></CITE>].=20 The combination of erlotinib followed by bortezomib had little activity. = The=20 EGFR receptor inhibitors cause G1 cell cycle arrest while temozolomide = causes=20 cell cycle arrest in G2-M [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR37">37</A></CITE>].=20 Erlotinib and gefitinib may prevent cells from progressing beyond G1 and = may=20 therefore compromise the activity of other cell cycle-specific agents, = such as=20 temozolomide. </P> <P class=3D"">At the time this trial was designed, the prognostic or = predictive=20 value of MGMT promoter methylation and the presence of PTEN and EGFRvIII = expression and of phosphorylated PKB/Akt were not known [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR27">27</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR39">39</A></CITE>].=20 Therefore these assays were not included in the design of this trial. = The tissue=20 available after the trial was complete was analysed for MGMT promoter=20 methylation status. Of the 10 patients for whom adequate amounts of = tissue were=20 available for analysis, in only four patients could suitable, full or = near-full=20 length genomic DNA be obtained to allow analysis of the MGMT promoter. = In each=20 of these four, at least one MGMT promoter site was methylated. It is = unclear=20 that these results affected response to therapy in these patients since = the=20 effect of methylation of one of more sites of the MGMT promoter on=20 post-transcriptional, translational and post-translational levels of the = protein=20 remains uncertain. This small cohort of patients may have included a = high=20 proportion of patients whose tumors had an unmethylated MGMT promoter. = The poor=20 response to erlotinib could have resulted from a high proportion of = patients=20 whose tumors lacked EGFRvIII or had wild type PTEN [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR26">26</A></CITE>].=20 In addition the poor outcomes could not be explained by an adverse = grouping of=20 patients in poor prognosis RPA groups. Finally, during the conduct of = this=20 trial, no concurrent trials at our institution selected out better = prognosis=20 patients in a manner that would have left predominantly poor prognosis = patients=20 available for this trial. </P> <P class=3D"">This trial had an unacceptably high number of deaths = prompting early=20 closure of the study. Three deaths were related to treatment: two = patients=20 developed refractory bone marrow aplasia and one developed PCP. The = latter=20 patient had no evidence of erolitinib-induced fibrosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR40">40</A></CITE>].=20 It is conceivable that prophylactic trimethoprim/sulfamethoxazole may = have=20 prevented this case of PCP, although no cases of PCP related to = temozolomide=20 have occurred at our institution. Erlotinib did not appear to exacerbate = the=20 toxicities of concurrent temozolomide and RT nor did the addition of = this agent=20 appear to cause the increased rate of death on this trial. </P> <P class=3D"">The combination of erlotinib with RT and temozolomide = using dose=20 escalation to a pharmacodynamic endpoint was feasible in patients with = newly=20 diagnosed GBM. The secondary objectives of testing the feasibility of=20 pharmacodynamic dose escalation and evaluating the toxicity of this = regimen were=20 met as the patients in this trial reached erlotinib dosing to the = predetermined=20 grade 2 rash. Since all patients developed a rash and most reached grade = 2,=20 correlation with efficacy was not possible. </P> <P class=3D"">In summary, this trial of the combination of RT, = temozolomide and=20 erlotinib for patients with newly diagnosed GBM was not efficacious and = had an=20 unacceptably high death rate. The lack of efficacy may have resulted = from=20 concurrent use of a cytostatic agent, which may cause cell cycle arrest, = with=20 the cytotoxic agents. Erlotinib-induced cytostatic cell cycle arrest may = reduce=20 or eliminate the sensitivity of GBM cells to radiation and temozolomide. = The=20 above theory is contrasted by two recent studies which have shown more=20 encouraging results using the regimen in this trial [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR42">42</A></CITE>].=20 These trials showed median survivals of 84 weeks and = 15 months,=20 respectively. The latter study, however, did not appear to benefit = patients when=20 compared to EORTC 26981 [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>].=20 The design of these trials was similar to the current study. The study = by Prados=20 had two cohorts according to the use or non-use of EIAEDs. In the = non-EIAED arm,=20 patients received erlotinib 100 mg/day during radiation therapy = with no=20 dose escalation during that phase. In the current study, patients = received a=20 lower dose, 50 mg/day, for the first two weeks of the study and = then=20 escalated to 100=96150 mg/day. Thus the dosing was very similar to = the=20 non-EIAED arm of that study. In the study by Brown, patients started RT = on=20 erlotinib alone for the first week before receiving full dose = combination=20 therapy. While these regimens have some differences, it is doubtful that = these=20 can explain the wide disparity in outcome between the three studies. = Future=20 studies with these agents administered on a different schedule, in = combination=20 with other tyrosine kinase inhibitors, or in patients selected for = factors, such=20 as MGMT methylation or EGFRvIII mutation, may lead to improved efficacy. = </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Henson JW (2006) Treatment of glioblastoma = multiforme:=20 a new standard. 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From: Subject: 10.1007/s11060-009-0067-2 Date: Fri, 25 Dec 2009 05:02:51 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0013_01CA851F.825A8050" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0013_01CA851F.825A8050 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.springerlink.com/content/l467p704762u5541/fulltext.html 10.1007/s11060-009-0067-2</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 6.00.6000.16945" 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. 2009</TD></TR> <TR> <TD>10.1007/s11060-009-0067-2</TD></TR></TBODY></TABLE> <H2 class=3Drubric>Clinical Study - Patient Study</H2> <DIV class=3DHeading1><A name=3Dtitle></A>Phase II trial of erlotinib = with=20 temozolomide and radiation in patients with newly diagnosed glioblastoma = multiforme </DIV> <P class=3DAuthorGroup>David M. Peereboom<SUP>1 <A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#ContactOfAuthor1"><IMG=20 alt=3D"Contact Information"=20 src=3D"http://www.springerlink.com/content/l467p704762u5541/contact.gif" = border=3D0></A></SUP>, Dale R. Shepard<SUP>2</SUP>,=20 Manmeet S. Ahluwalia<SUP>1</SUP>,=20 Cathy J. Brewer<SUP>1</SUP>, Neeraj Agarwal<SUP>1</SUP>,=20 Glen H. J. Stevens<SUP>1</SUP>, = John H. Suh<SUP>1,=20 3</SUP>, Steven A. Toms<SUP>4</SUP>,=20 Michael A. Vogelbaum<SUP>1</SUP>,=20 Robert J. Weil<SUP>1</SUP>, Paul Elson<SUP>5</SUP> and=20 Gene H. Barnett<SUP>1</SUP></P> <TABLE> <TBODY> <TR vAlign=3Dtop> <TD><SPAN class=3DAffiliation><A = name=3DAff1></A>(1) </SPAN></TD> <TD><SPAN class=3DAffiliation>Brain Tumor and Neuro-Oncology Center, = Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, = Cleveland,=20 OH 44195, USA</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>Solid Tumor Oncology, Cleveland = Clinic, 9500=20 Euclid Ave, Cleveland, OH 44195, = USA</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>Radiation Oncology, Cleveland Clinic, = 9500=20 Euclid Ave, Cleveland, OH 44195, = USA</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>Neurosurgery, Geisinger Health System, = Danville, PA, USA</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>Quantitative Health Services, = Cleveland=20 Clinic, 9500 Euclid Ave, Cleveland, OH, = USA</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/l467p704762u5541/contact.gif" = border=3D0></TD> = <TD><STRONG>David </STRONG><STRONG>M. </STRONG><STRONG>Peereboo= m</STRONG><STRONG></STRONG><BR><STRONG>Email:=20 </STRONG><A=20 href=3D"mailto:peerebd@ccf.org">peerebd@ccf.org</A></TD></TR></TBODY></TA= BLE> <P class=3DAffiliation><STRONG>Received:=20 </STRONG>23 July 2009 <STRONG>Accepted:=20 </STRONG>9 November 2009 <STRONG>Published online:=20 </STRONG>4 December 2009 </P> <DIV class=3DAbstract><A name=3DAbs1></A><SPAN=20 class=3DAbstractHeading>Abstract </SPAN>Approximately = 40=9650% of=20 glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). = Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active = against=20 refractory GBM. Patients with non-small cell lung cancer and = ≥grade 2=20 erlotinib-induced rash have improved survival. This phase 2 study = assessed the=20 efficacy and safety of concurrent radiation therapy (RT) and = temozolomide with=20 pharmacodynamic dose escalation of erlotinib in patients with newly = diagnosed=20 GBM. Patients received RT 60 Gy in 30 fractions with concurrent=20 temozolomide 75 mg/m<SUP>2</SUP>/day =D7 42 days, = followed in=20 four weeks by temozolomide = 150=96200 mg/m<SUP>2</SUP>/day =D7 5,=20 every 28 days for 12 cycles. Patients received erlotinib, = 50 mg/day=20 and increased by 50 mg/day every 2 weeks until the occurrence = of grade=20 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease = progression. Twenty-seven patients were treated in this study. = Twenty-two (81%)=20 patients came off study for progressive disease (18 [67%]) or adverse = events (4=20 [15%]). Eighteen patients (67%) have died. Median progression-free = survival was=20 2.8 months, and the median overall survival was 8.6 months. = Five=20 patients remain on study with a median follow-up of 16 months. = Grade 3/4=20 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and = febrile=20 neutropenia. There were four deaths on study, three definitely=20 treatment-related; therefore, the trial was terminated after accrual of = 27 of 30=20 planned patients. Erlotinib co administered with RT and temozolomide was = not=20 efficacious and had an unacceptable toxicity. </DIV> <P class=3DKeyword><SPAN = class=3DKeywordHeading>Keywords </SPAN>EGFR=20 inhibitor - Temozolomide - Erlotinib - Glio= blastoma=20 multiforme - Newly=20 diagnosed - Chemotherapy - Efficacy - Phase= II=20 </P> <DIV class=3DFulltext> <DIV class=3D""><A name=3DSec1></A> <HR> <DIV class=3Dheading2>Introduction</DIV> <P class=3D"">Glioblastoma multiforme (GBM) is an aggressive primary = tumor of the=20 central nervous system accounting for about 50% of all adult gliomas = [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR1">1</A></CITE>].=20 Based on a significant survival advantage provided by the use of = concurrent=20 chemo-radiotherapy and adjuvant chemotherapy with temozolomide = demonstrated in a=20 recent phase III trial, this regimen is now considered to be standard of = care=20 for newly diagnosed GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>].=20 Despite an improvement in overall survival (OS) with this regimen, the = prognosis=20 of patients with GBM remains poor with a median OS of 9 to = 15 months and a=20 2-year survival rate of 9=9626% [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR3">3</A></CITE>].=20 </P> <P class=3D"">Approximately 40=9650% of GBM overexpress epidermal growth = factor=20 receptor (EGFR), a type I receptor tyrosine kinase correlated with an = aggressive=20 phenotype [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR4">4</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR6">6</A></CITE>].=20 EGFR activates an intracellular tyrosine kinase that leads to a signal=20 transduction cascade that enhances survival and infiltration of GBM = cells in=20 vitro [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR8">8</A></CITE>].=20 Overexpression of EGFR correlates with increased cellular proliferation, = tumorigenesis, decreased apoptosis, and a poor prognosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR5">5</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR7">7</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR9">9</A></CITE>].=20 In addition, EGFR overexpression in GBM correlates with radioresistance=20 [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR10">10</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR11">11</A></CITE>].=20 </P> <P class=3D"">Erlotinib (Tarceva=99) is a specific, potent inhibitor of = EGFR=20 tyrosine kinase with antitumor activity in lung and pancreatic cancer = [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR12">12</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR13">13</A></CITE>].=20 In preclinical studies in GBM cell lines, erlotinib suppressed=20 anchorage-independent growth, had antiproliferative and apoptotic = effects, and=20 had activity against cell lines that harbor the EGFRvIII mutant receptor = [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR14">14</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR15">15</A></CITE>].=20 Erlotinib alone or with temozolomide has antitumor activity in phase I = or II=20 studies with patients with stable or refractory GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR17">17</A></CITE>].=20 Erlotinib was well tolerated in phase I trials of patients with solid=20 malignancies, including newly diagnosed GBM; grade 3 rash, fatigue, = diarrhea, or=20 stomatitis occurred in 5=9615% of patients [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR16">16</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR18">18</A></CITE>].=20 </P> <P class=3D"">In this study, we investigated the efficacy and safety of = erlotinib=20 in combination with the standard regimen of temozolomide and = radiotherapy (RT)=20 in patients with newly diagnosed GBM. In studies of erlotinib in = patients with=20 non-small cell lung cancer, survival correlated with development of = grade 2 skin=20 rash, suggesting a physiologic marker for maximal dose [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR19">19</A></CITE>].=20 The primary objective of this trial was to determine progression free = survival=20 (PFS) and OS. Toxicity and the feasibility of pharmacodynamic dose = escalation=20 were secondary objectives. </P></DIV> <DIV class=3D""><A name=3DSec2></A> <HR> <DIV class=3Dheading2>Methods</DIV> <DIV class=3D""><A name=3DSec3></A> <DIV class=3DHeading3>Patients</DIV> <P class=3D"">Patients with histologically-proven, newly diagnosed GBM = who were=20 within 28 days of their diagnostic biopsy or resection, were at = least=20 18 years old, and with a Karnofsky performance score of at least 60 = were=20 eligible for this IRB-approved study. Prior administration of = temozolomide,=20 tyrosine kinase inhibitors, or cranial radiation, or concurrent = administration=20 of hepatic cytochrome P-450 enzyme-inducing antiepileptic drugs (EIAEDs) = such as=20 phenytoin, carbamazepine, phenobarbital, felbamate, oxycarbazepine, or=20 topiramate were not allowed. Patients on EIAEDs were transitioned to=20 levetiracetam prior to starting the trial. An absolute neutrophil=20 count >1.5 =D7 10<SUP>9</SUP> per liter, a platelet = count=20 >100 =D7 10<SUP>9</SUP> per liter; hemoglobin = >90 g/l, serum=20 creatinine and total serum bilirubin <1.5 times the upper limit of = normal,=20 aspartate aminotransferase or alanine aminotransferase <2.5 times the = upper=20 limit of normal, and alkaline phosphatase <2.5 times the upper limit = of=20 normal were required. Patients of reproductive potential were required = to use=20 effective contraception. Written informed consent was required prior to=20 treatment. </P> <P class=3D"">Patients with a severe underlying disease, including human = immunodeficiency virus or chronic hepatitis B or C infection were = excluded.=20 Other antineoplastic therapy during study drug administration was = prohibited.=20 Women who were pregnant or breast feeding were excluded. Patients with = any=20 malignancy within 3 years with the exception of surgically cured=20 carcinoma-in situ of the cervix, non-melanoma skin cancer, or adequately = treated=20 stage I or II cancer in complete remission were excluded. Demonstration = of EGFR=20 expression by the tumor or presence of measurable disease on = neuroimaging was=20 not required for enrollment in the trial. </P></DIV> <DIV class=3D""><A name=3DSec4></A> <DIV class=3DHeading3>Study design</DIV> <P class=3D"">All patients were treated at the Cleveland Clinic. RT was=20 administered in 2 Gy/day fractions, 5 days per week, to a = total of=20 60 Gy over six weeks. The target volume for the initial and = cone-down=20 volume was based on the post-operative MRI. The initial target volume = included=20 the edema on T2 sequences plus a 2.0-cm margin; if no edema was present, = a=20 2.5 cm margin beyond the contrast-enhanced lesion and resection = cavity was=20 treated. The initial target volume was treated with 46 Gy in 23 = fractions.=20 The cone-down tumor volume included the resection cavity with = contrast-enhancing=20 lesion plus a 2.5-cm margin. </P> <P class=3D"">Temozolomide administration began on day 1 of RT at=20 75 mg/m<SUP>2</SUP>/day and continued for 42 days. = Temozolomide was=20 taken while fasting, 1 h before RT, and in the morning on days = without RT.=20 All patients received a single inhaled dose of pentamidine for = prophylaxis=20 against pneumocystis pneumonia during weeks 1 and 4 of RT. The initial = dose of=20 erlotinib was 50 mg/day, beginning on Day 1 of RT, with escalation = by=20 50 mg/day every 2 weeks until the occurrence of an = erlotinib-induced=20 grade 2 or greater rash outside the radiation field or a maximum dose of = 150 mg/day. Erlotinib was continued until disease progression. = Patients who=20 developed seizures were treated with non-EIAEDs. Grade 2 or higher skin = rash was=20 treated with minocycline, topical tetracycline, topical retinoids or = oral=20 antibacterial agents. </P> <P class=3D"">An MRI was obtained four weeks after completion of RT as a = baseline.=20 Patients received temozolomide daily for 5 days during every = 28 day=20 cycle for up to 12 cycles. Patients received temozolomide=20 150 mg/m<SUP>2</SUP>/day for 5 days for cycle 1. In the = absence of=20 grade 3 or 4 neutropenia or thrombocytopenia during cycle 1, patients = received=20 temozolomide 200 mg/m<SUP>2</SUP>/day for 5 days for 11 = additional=20 cycles. CBCs were monitored weekly during weeks 3=966 of radiation = therapy and=20 subsequently on day 1 of each post-radiation cycle of therapy. = Compliance with=20 this schedule of monitoring was estimated to be at least 95%. </P> <P class=3D"">Hematopoietic growth factors were only used in patients = with=20 persistent refractory neutropenia. Prophylactic antiemetics were used = during RT=20 at the discretion of the investigator. Anticonvulsants and = corticosteroids were=20 administered as needed with EIAEDs avoided if possible. Patients who=20 inadvertently received EIAEDs during the study transitioned to = non-EIAEDs as=20 soon as feasible. </P></DIV> <DIV class=3D""><A name=3DSec5></A> <DIV class=3DHeading3>Dose reductions</DIV> <P class=3D"">During RT, temozolomide was held and not restarted for an=20 ANC<1500/μl or platelets <100,000/μl. There was no dose = reduction for=20 temozolomide during RT. During post-RT temozolomide, the cycle was = initiated=20 once ANC <U>></U>1500 and platelets <U>></U>100,000. In = patients=20 with grade 3 temozolomide-related toxicity, temozolomide was held until = the=20 toxicity returned to grade 0=961. If the ANC nadir from the previous = cycle=20 was <500 and/or platelet nadir was <20,000, the = temozolomide=20 dose was decreased by 25% for the subsequent cycle. For reversible, = grade 4=20 non-hematological temozolomide-related toxicity, the temozolomide dose = was=20 reduced to 80% of the dose for the previous cycle for all subsequent = cycles. If=20 temozolomide-related toxicity did not resolve within 2 weeks or if = the=20 toxicity was not tolerated, temozolomide was discontinued, but any = remaining RT=20 and erlotinib was given. </P> <P class=3D"">Erlotinib was held for grade <U>></U>3 rash until=20 improvement to grade ≤2 and resumed with a 50 mg/day dose = reduction. If=20 erlotinib-related toxicity did not resolve within 2 weeks or the = toxicity=20 was intolerable, erlotinib was discontinued but any remaining RT and=20 temozolomide was given. </P></DIV> <DIV class=3D""><A name=3DSec6></A> <DIV class=3DHeading3>Assessment of response and safety</DIV> <P class=3D"">Patients were removed from the study for unacceptable = toxicity or=20 toxicity leading to discontinuation of both temozolomide and erlotinib. = Other=20 criteria for study discontinuation were patient choice, noncompliance, = serious=20 concurrent illness, or progressive disease. Progressive disease was = defined as=20 <U>></U>25% increase in the sum of the products of all T1 weighted=20 gadolinium-enhancing measurable disease compared with the baseline = measurement,=20 or the appearance of new lesions. A PET scan, blood volume MRI or tissue = biopsy=20 were attempted, if necessary, to distinguish tumor growth from=20 pseudo-progression. Cases of possible progression were also reviewed as=20 necessary at a multidisciplinary brain tumor conference. </P> <P class=3D"">Physical examinations, assessment of routine labs, and = evaluation of=20 toxicity were conducted prior to the study and at scheduled intervals = throughout=20 the study. A gadolinium-enhanced MRI of brain was performed within = 3 weeks=20 before starting radiation and before cycles 1, 3, 5, 7, 9, and 11 of = post=20 radiation temozolomide. An MRI was obtained every 2 months during = the first=20 year after completion of temozolomide and every 3 months = thereafter.=20 </P></DIV> <DIV class=3D""><A name=3DSec7></A> <DIV class=3DHeading3>Statistical methods</DIV> <P class=3D"">The primary endpoints of the study were PFS and OS. = Assuming a=20 6-month PFS of 50%, based on historical controls, it was estimated that = 30=20 patients would need to be assessed and followed for at least six months = in order=20 to have 80% power, based on a 2-sided <I>P</I> =3D .05 exact = binomial=20 test, to detect an increase in PFS to 75% [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR20">20</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR22">22</A></CITE>].=20 </P> <P class=3D"">With 30 patients, the incidence of specific toxicities, = and key=20 quantiles such as 6-month and 1-year PFS and OS could be estimated using = 95%=20 confidence intervals with maximum half-widths of 19%. PFS and OS were = calculated=20 from the date of study entry to the date of disease progression, death, = or final=20 follow-up and were summarized using the method of Kaplan and Meier. If = the=20 underlying incidence for a specific toxicity was <U><</U>5%, there = was=20 a <U>></U>79% chance of observing the toxicity in at least one = of the 30=20 patients enrolled in the study. Statistical significance was defined as=20 <I>P</I> < 0.05 and statistical tests were two-sided. All = analyses=20 were conducted using SAS<SUP>=AE</SUP> version 8.0 software (SAS = Institute, Inc.,=20 Cary, NC). </P></DIV> <DIV class=3D""><A name=3DSec8></A> <DIV class=3DHeading3>Methyl guanine methyl transferase (MGMT) promoter=20 methylation analysis</DIV> <P class=3D"">Nested polymerase chain reaction (PCR) was used for = amplification of=20 bisulfite treated genomic DNA. First round PCR MGMT primers: forward is=20 TTTTTTTGTTTTTTTTAGGTTTT and reverse is AACCTAAAACTAACACCTAAAAA. The = annealing=20 temperature was 45=B0C. The second round PCR MGMT primers: forward is=20 CCTAATGTTGGGATAGTT, reverse is CAACATCACTAACACCTAACC, and the annealing=20 temperature was 60=B0C. Second reverse primer sequences are derived from = Parkinson=20 et al. and from the NCBI sequence site; primer sequences are available = on=20 request [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR23">23</A></CITE>].=20 Platinum <I>Taq</I>DNA Polymerase (Invitrogen, California, USA) was used = according to the manufacturer=92s instructions. PCR amplicons were = purified using=20 QIAquick PCR Purification Kit PCR (QIAGEN Inc. Valencia, California, = USA).=20 Sequencing was performed in forward and reverse directions using the = same=20 primers as those used for the second round PCR, according to standard=20 techniques. Colon cancer line SW48, in which all 28 promoter sites are=20 methylated was used as a positive control. </P></DIV></DIV> <DIV class=3D""><A name=3DSec9></A> <HR> <DIV class=3Dheading2>Results</DIV> <DIV class=3D""><A name=3DSec10></A> <DIV class=3DHeading3>Patient characteristics</DIV> <DIV class=3DPara> <DIV class=3D"">Twenty-eight patients were enrolled between December = 2003 and=20 December 2005. One patient did not receive treatment and was excluded = from all=20 efficacy and safety analyses. Among the 27 evaluable patients, the = median age=20 was 52 years and the median Karnofsky performance status (KPS) was = 90=20 (Table <A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#Tab1">1</A>).=20 Eight patients had gross total resection, eight had subtotal resection, = and 11=20 had biopsy only. RPA grouping was as follows: group III=9611 patients; = group IV=967;=20 and group V=969 [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR24">24</A></CITE>].=20 EGFR was amplified in 9 patients, not amplified in 17 patients, and not=20 determined in 1 patient.<A name=3DTab1></A> <DIV class=3DCapt><SPAN class=3DCaptNr>Table 1 </SPAN>Patient = demographics=20 </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"("></COLGROUP> <THEAD> <TR class=3Dheader> <TH align=3Dleft> <P class=3D"">Characteristic</P></TH> <TH align=3Dleft char=3D"("> </TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Age, years (median, range)</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">52 (18=9674)</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""> Men</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">17 (63)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Women</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">10 (37)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Karnofsky performance status (<I>n</I>, %) = </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 90=96100</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">18 (67)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> 60=9680</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (33)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">Extent of surgery (<I>n</I>, %) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Gross total resection</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Subtotal resection</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">8 (30)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Biopsy only</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">11 (40)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft colSpan=3D2> <P class=3D"">EGFR status (<I>n</I> =3D 26) (<I>n</I>, = %) </P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Amplified</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">9 (35)</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D""> Negative</P></TD> <TD align=3Dchar char=3D"("> <P class=3D"">17 = (65)</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec11></A> <DIV class=3DHeading3>Efficacy</DIV> <P class=3D"">Twenty of the 27 patients (74%) completed the first = 42 day=20 treatment period during which chemotherapy was given concurrently with=20 radiation, with no dose modifications. Three patients had treatment = delayed, and=20 four patients discontinued treatment with erlotinib and/or temozolomide = due to=20 toxicity. Thirteen patients (48%) continued on treatment post radiation = and=20 received a median of five cycles of therapy (range 1=9618+). </P> <P class=3D"">Twenty-two (81%) patients had progressive disease and 4 = (15%)=20 patients came off study for adverse events. Eighteen patients (67%) have = died.=20 The 6-month progression free survival was 30%, and the median = progression-free=20 survival was 2.8 months. The median overall survival was = 8.6 months.=20 Five patients remain on study with a median follow-up of 16 months = (range=20 9.7=9621.5 months). </P> <P class=3D"">There was a trend but no statistical correlation between = efficacy=20 and EGFR amplification. The overall survival of those with and without = EGFR=20 amplification was 11 months and 8 months, respectively=20 (<I>P</I> =3D 0.13). The failure free survival of those with = and without=20 EGFR amplification was 5.9 months and 2.6 months, respectively = (<I>P</I> =3D 0.16). </P></DIV> <DIV class=3D""><A name=3DSec12></A> <DIV class=3DHeading3>Toxicity</DIV> <DIV class=3DPara> <DIV class=3D"">The maximum dose of erlotinib reached before the = occurrence of=20 grade 2 rash was 50 mg/day in one patient, 100 mg/day in five=20 patients, and 150 mg/day in 21 patients. Four deaths occurred = during the=20 study, three of which were definitely related to treatment. Three deaths = occurred in the last four patients accrued to the trial with termination = of the=20 trial after enrolling 27 of the 30 planned patients. One patient died of = pneumocystis carinii pneumonia (PCP), confirmed by bronchoscopy, despite = prophylaxis with pentamidine. Two patients died of refractory bone = marrow=20 aplasia and one died of non-neutropenic sepsis. Treatment-related Grade = 3 or 4=20 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and = febrile=20 neutropenia (Table <A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#Tab2">2</A>).<A=20 name=3DTab2></A> <DIV class=3DCapt><SPAN = class=3DCaptNr>Table 2 </SPAN>Treatment-related=20 adverse events </DIV> <TABLE border=3D1> <COLGROUP> <COL align=3Dleft> <COL align=3Dchar char=3D"."> <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> <P class=3D"">Adverse event (27 patients)</P></TH> <TH align=3Dleft colSpan=3D4 char=3D"."> <P class=3D"">Grade (n)</P></TH></TR> <TR class=3Dheader> <TH align=3Dleft char=3D"."> <P class=3D"">1=962</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">3</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">4</P></TH> <TH align=3Dleft char=3D"."> <P class=3D"">5</P></TH></TR></THEAD> <TBODY> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Neutropenia with fever</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Sepsis without neutropenia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Pneumocystis pneumonia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Neutropenia without fever</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Thrombocytopenia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">4</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Lymphopenia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">15</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Anemia</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">6</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">3</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">1</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">ALT increase</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">10</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR> <TR class=3Dnoclass> <TD align=3Dleft> <P class=3D"">Fatigue</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">23</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">2</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD> <TD align=3Dchar char=3D"."> <P class=3D"">0</P></TD></TR></TBODY></TABLE></DIV></DIV></DIV> <DIV class=3D""><A name=3DSec13></A> <DIV class=3DHeading3>MGMT promoter methylation analysis</DIV> <P class=3D"">Adequate paraffin-embedded tissue was available for 10 = patients.=20 After appropriate processing and digestion, suitable genomic DNA for = analysis=20 was obtained in four patients. Each of the four patients in whom = adequate DNA=20 was available for bisulfite methylation analysis showed methylation of = at least=20 one of 28 potential <I>MGMT</I> promoter sites (range, 1=9617 sites = methylated;=20 average of seven sites; median value five sites). </P></DIV></DIV> <DIV class=3D""><A name=3DSec14></A> <HR> <DIV class=3Dheading2>Discussion</DIV> <P class=3D"">The goal of this study was to estimate the PFS and OS in = patients=20 with newly diagnosed GBM treated with erlotinib and RT-temozolomide. The = primary=20 objective of 6-month PFS of 75% was not met. In this study the 6-month = PFS was=20 30%, the median PFS was 2.8 months, and the median OS was = 8.6 months.=20 These results are substantially worse than the median PFS of = 6.9 months and=20 the OS of 14.6 months for patients who receive RT with concurrent=20 temozolomide [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>].=20 The short PFS might raise the question as to whether patients were taken = off=20 study prematurely for pseudo-progression [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR25">25</A></CITE>].=20 Cases in question were reviewed by a multidisciplinary brain tumor = board. At=20 least one patient had a biopsy performed which confirmed progression. = The short=20 overall survival of patients in this study also speaks against=20 pseudo-progression as a significant event for patients in this trial. = </P> <P class=3D"">Although inhibition of EGFR with receptor tyrosine kinase=20 inhibitors, such as erlotinib or gefitinib showed promise when this = study was=20 designed, these agents have subsequently shown only moderate activity as = single=20 agents in patients with GBM [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR17">17</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR26">26</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR29">29</A></CITE>].=20 In one trial, 10 of 24 (42%) patients with recurrent or progressive GBM=20 receiving erlotinib had a partial response or stable disease with a = median time=20 to progression of about 4.5 months [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR17">17</A></CITE>].=20 Analogous results were observed with EGFR antagonists in patients with = non-small=20 cell lung cancer in that second and third line therapy with single agent = gefitinib or erlotinib produced survival benefits while these agents = combined=20 with standard cytotoxic regimens as first-line therapy for metastatic = disease=20 showed no benefit [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR30">30</A></CITE>=96<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR32">32</A></CITE>].=20 </P> <P class=3D"">There are several proposed mechanisms for the poor = efficacy of=20 single agent erlotinib and the antagonism of erlotinib in combination = with=20 chemotherapy. Although activation of EGFR is important for the = activation of=20 phosphatidylinositol 3-kinase (PI3K) and Akt, numerous receptor kinases = may be=20 activated by GBM cells and treatment with a single tyrosine kinase = inhibitor,=20 such as erlotinib, is not sufficient to decrease cell signaling and=20 anchorage-independent growth [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR33">33</A></CITE>].=20 One potential mechanism for antagonism is that EGFR inhibitors, such as=20 erlotinib, may cause cell cycle arrest thereby making cells less = sensitive to=20 the cell cycle dependent effects of radiation therapy and temozolomide. = In vitro=20 and preclinical studies have shown schedule dependent interactions = between the=20 EGFR inhibitors and chemotherapy. The tyrosine kinase inhibitor = gefitinib=20 significantly improved the antitumor activity of paclitaxel in a human = mammary=20 carcinoma xenograft model, but only when gefitinib was given on a = pulsatile=20 schedule, not with continuous dosing [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR34">34</A></CITE>].=20 Similarly, the cytotoxicity of erlotinib with pemetrexed in NSCLC cells = was=20 synergistic when administered together or with pemetrexed followed by = erlotinib,=20 however there was antagonistic activity when erlotinib was administered = prior to=20 pemetrexed in erlotinib-sensitive cells [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR35">35</A></CITE>].=20 The combination of erlotinib and bortezomib had additive cytotoxicity in = the=20 H358 bronchioalveolar cell line, but there was schedule dependence with = the=20 additive effect only when the two agents were used together or = bortezomib was=20 added first [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR36">36</A></CITE>].=20 The combination of erlotinib followed by bortezomib had little activity. = The=20 EGFR receptor inhibitors cause G1 cell cycle arrest while temozolomide = causes=20 cell cycle arrest in G2-M [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR37">37</A></CITE>].=20 Erlotinib and gefitinib may prevent cells from progressing beyond G1 and = may=20 therefore compromise the activity of other cell cycle-specific agents, = such as=20 temozolomide. </P> <P class=3D"">At the time this trial was designed, the prognostic or = predictive=20 value of MGMT promoter methylation and the presence of PTEN and EGFRvIII = expression and of phosphorylated PKB/Akt were not known [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR27">27</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR38">38</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR39">39</A></CITE>].=20 Therefore these assays were not included in the design of this trial. = The tissue=20 available after the trial was complete was analysed for MGMT promoter=20 methylation status. Of the 10 patients for whom adequate amounts of = tissue were=20 available for analysis, in only four patients could suitable, full or = near-full=20 length genomic DNA be obtained to allow analysis of the MGMT promoter. = In each=20 of these four, at least one MGMT promoter site was methylated. It is = unclear=20 that these results affected response to therapy in these patients since = the=20 effect of methylation of one of more sites of the MGMT promoter on=20 post-transcriptional, translational and post-translational levels of the = protein=20 remains uncertain. This small cohort of patients may have included a = high=20 proportion of patients whose tumors had an unmethylated MGMT promoter. = The poor=20 response to erlotinib could have resulted from a high proportion of = patients=20 whose tumors lacked EGFRvIII or had wild type PTEN [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR26">26</A></CITE>].=20 In addition the poor outcomes could not be explained by an adverse = grouping of=20 patients in poor prognosis RPA groups. Finally, during the conduct of = this=20 trial, no concurrent trials at our institution selected out better = prognosis=20 patients in a manner that would have left predominantly poor prognosis = patients=20 available for this trial. </P> <P class=3D"">This trial had an unacceptably high number of deaths = prompting early=20 closure of the study. Three deaths were related to treatment: two = patients=20 developed refractory bone marrow aplasia and one developed PCP. The = latter=20 patient had no evidence of erolitinib-induced fibrosis [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR40">40</A></CITE>].=20 It is conceivable that prophylactic trimethoprim/sulfamethoxazole may = have=20 prevented this case of PCP, although no cases of PCP related to = temozolomide=20 have occurred at our institution. Erlotinib did not appear to exacerbate = the=20 toxicities of concurrent temozolomide and RT nor did the addition of = this agent=20 appear to cause the increased rate of death on this trial. </P> <P class=3D"">The combination of erlotinib with RT and temozolomide = using dose=20 escalation to a pharmacodynamic endpoint was feasible in patients with = newly=20 diagnosed GBM. The secondary objectives of testing the feasibility of=20 pharmacodynamic dose escalation and evaluating the toxicity of this = regimen were=20 met as the patients in this trial reached erlotinib dosing to the = predetermined=20 grade 2 rash. Since all patients developed a rash and most reached grade = 2,=20 correlation with efficacy was not possible. </P> <P class=3D"">In summary, this trial of the combination of RT, = temozolomide and=20 erlotinib for patients with newly diagnosed GBM was not efficacious and = had an=20 unacceptably high death rate. The lack of efficacy may have resulted = from=20 concurrent use of a cytostatic agent, which may cause cell cycle arrest, = with=20 the cytotoxic agents. Erlotinib-induced cytostatic cell cycle arrest may = reduce=20 or eliminate the sensitivity of GBM cells to radiation and temozolomide. = The=20 above theory is contrasted by two recent studies which have shown more=20 encouraging results using the regimen in this trial [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR41">41</A></CITE>,=20 <CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR42">42</A></CITE>].=20 These trials showed median survivals of 84 weeks and = 15 months,=20 respectively. The latter study, however, did not appear to benefit = patients when=20 compared to EORTC 26981 [<CITE><A=20 href=3D"http://www.springerlink.com/content/l467p704762u5541/fulltext.htm= l#CR2">2</A></CITE>].=20 The design of these trials was similar to the current study. The study = by Prados=20 had two cohorts according to the use or non-use of EIAEDs. In the = non-EIAED arm,=20 patients received erlotinib 100 mg/day during radiation therapy = with no=20 dose escalation during that phase. In the current study, patients = received a=20 lower dose, 50 mg/day, for the first two weeks of the study and = then=20 escalated to 100=96150 mg/day. Thus the dosing was very similar to = the=20 non-EIAED arm of that study. In the study by Brown, patients started RT = on=20 erlotinib alone for the first week before receiving full dose = combination=20 therapy. While these regimens have some differences, it is doubtful that = these=20 can explain the wide disparity in outcome between the three studies. = Future=20 studies with these agents administered on a different schedule, in = combination=20 with other tyrosine kinase inhibitors, or in patients selected for = factors, such=20 as MGMT methylation or EGFRvIII mutation, may lead to improved efficacy. = </P></DIV> <P></P> <HR> <H2><A name=3DBib1></A>References </H2> <TABLE> <TBODY class=3DCitation> <TR vAlign=3Dtop> <TD>1.</TD> <TD><A name=3DCR1></A>Henson JW (2006) Treatment of glioblastoma = multiforme:=20 a new standard. 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