glioblastoma multiforme ( gbm ) is a neoplasm with variable features not only histologically but also biologically .
gbm is characterized by diverse imaging features , including highly heterogeneous enhancement , reflecting variable disruption of the blood brain barrier ( bbb ) and inherent differences in the vascularity of the tumor .
bevacizumab , a monoclonal antibody against vascular endothelial growth factor ( vegf ) , has been used most commonly in combination with irinotecan or other cytotoxic agents as salvage therapy .
our case report vividly demonstrates disparate responses to combined biochemotherapy in the same patient with recurrent gbm .
two synchronous foci of recurrent disease , one area with enhancement and another one nonenhancing and infiltrative , responded differently to treatment with bevacizumab and irinotecan .
this case illustrates the principle of antiangiogenesis mechanisms in the treatment of enhancing gbm , and provides a dramatic example of the heterogeneity of the tumor biology and its different responses to treatment .
a 42-year - old , right - handed , previously healthy man presented with one week of morning headaches , general weakness , vertigo , nausea , and vomiting .
his neurological examination revealed a mild pronator drift of the right upper limb , without other abnormalities .
brain magnetic resonance imaging ( mri ) showed an enhancing right frontotemporal tumor ( figure 1 ) .
the pathology was typical for gbm , with nuclear atypia , multiple mitotic divisions , vascular endothelial proliferation , and focal tumor necrosis . 

figure 1(a ) initial preoperative magnetic resonance imaging ( mri ) scan : axial t1-weighted sequence with gadolinium demonstrates a right temporal , centrally hypointense lesion with mass effect and midline shift .
( b ) axial t1-weighted sequence mri with gadolinium following the second operation , postradiation , demonstrates a cystic cavity with postsurgical changes , resolution of mass effect , and shift . 
 
( a ) initial preoperative magnetic resonance imaging ( mri ) scan : axial t1-weighted sequence with gadolinium demonstrates a right temporal , centrally hypointense lesion with mass effect and midline shift .
( b ) axial t1-weighted sequence mri with gadolinium following the second operation , postradiation , demonstrates a cystic cavity with postsurgical changes , resolution of mass effect , and shift .
the patient began standard chemoradiation ( conformal external beam radiation , 200 cgy per fraction , with concomitant temozolomide 75 mg / m per day ) .
two weeks into his treatment , he was admitted to the emergency room with headache , vertigo , and a new left homonymous hemianopsia . a brain computerized tomography ( ct ) scan revealed early recurrence of the tumor with significant vasogenic edema and midline shift .
the patient underwent a repeat right temporal craniotomy with gross total removal of the recurrent tumor and implantation of gliadel wafers .
after resolution of postoperative complications he completed hypofractionated radiation with concurrent temozolomide , and went on to receive 16 adjuvant cycles of monthly temozolomide .
he enjoyed good quality of life throughout this period , with his only symptoms being hemianopsia and mild impulsive behavior .
brain mri performed after the sixteenth cycle of adjuvant chemotherapy showed recurrent , enhancing , multifocal disease involving the right frontoparietal lobes , and nonenhancing involvement of the contralateral , left medial temporal lobe ( figures 2a and c ) .
these changes were predated by progressive cognitive decline , behavioral changes , and gait instability .
the patient was started on a salvage protocol of intravenous irinotecan and bevacizumab , 125 mg / m and 5 mg / kg , respectively , every two weeks .
after four treatments ( over two months ) his mri scan showed dramatic , almost complete resolution of the enhancing component of his disease ( figure 2b ) , but further progression of the ill - defined , nonenhancing , infiltrative , left medial temporal tumor ( figure 2d ) .
clinically , he became progressively confused , displayed dressing apraxia , increased emotional lability , impulsiveness , and loss of insight .
a fifth treatment of biochemotherapy was given with the addition of carboplatin auc 5 , but the patient continued to decline clinically , and he was transferred to hospice , where he died of progressive disease . 

figure 2(a ) t1-gadolinium fspgr magnetic resonance imaging ( mri ) scan , revealing a recurrent right frontoparietal focus before treatments with irinotecan and bevacizumab .
( b ) t1-gadolinium fspgr mri , post four treatments with irinotecan and bevacizumab demonstrating almost complete resolution of the enhancing disease .
( c ) t2 flair mri sequence revealing the medial left temporal nonenhancing focus pre irinotecan and bevacizumab treatment .
( d ) t2 flair mri sequence post irinotecan and bevacizumab treatment demonstrating progression of the ill - defined , nonenhancing , infiltrative left medial temporal lobe disease ( despite dramatic response of the right - sided disease as depicted in b ) . 
 
( a ) t1-gadolinium fspgr magnetic resonance imaging ( mri ) scan , revealing a recurrent right frontoparietal focus before treatments with irinotecan and bevacizumab .
( b ) t1-gadolinium fspgr mri , post four treatments with irinotecan and bevacizumab demonstrating almost complete resolution of the enhancing disease .
( c ) t2 flair mri sequence revealing the medial left temporal nonenhancing focus pre irinotecan and bevacizumab treatment .
( d ) t2 flair mri sequence post irinotecan and bevacizumab treatment demonstrating progression of the ill - defined , nonenhancing , infiltrative left medial temporal lobe disease ( despite dramatic response of the right - sided disease as depicted in b ) .
the natural history of recurrent gbm is variable , as the tumor is biologically heterogeneous .
we are only beginning to understand the molecular genetic components and distinct mechanisms that may determine a given neoplasm 's behavior and response to various treatments .
recent studies have shown the importance of a variety of molecular characteristics , including methylation of the methylguanine methyltransferase enzyme ( mgmt ) promoter , epidermal growth factor receptor ( egfr ) viii and phosphatase and tensin homolog ( pten ) status , and likely , the status of vegf and vegf receptor in relation to tumor growth and treatment responses .
targeting of tumor angiogenesis is a recently developed method for tumor control and stabilization , which shows promise in the treatment of several tumor types including malignant glioma .
biochemotherapy with bevacizumab and cytotoxic agents ( including irinotecan ) has been shown to improve survival significantly in patients with non - small - cell lung cancer and metastatic colorectal cancer .
use of antiagiogenic agents with chemotherapy has been shown to be effective in recurrent gbm as well .
the initial report by stark - vance using combined bevacizumab and irinotecan in the treatment of recurrent gbm demonstrated an unprecedented high response rate .
these findings were supported in phase ii trials of bevacizumab and irinotecan in recurrent malignant glioma , which led to fda approval of bebacizumab for second - line treatment of recurrent or progressive gbm in may 2009 .
a phase ii randomized , noncomparative clinical trial of bevacizumab alone or in combination with irinotecan in a group of 167 patients revealed six months of progression free survival ( pfs ) of 42.6% and 50.3% in the bevacizumab arm alone and in combination with irinotecan , respectively , with 9.2 months , with bevacizumab alone and 8.7 months median survival with combined therapy .
bokstein , et al . reported a series of 20 patients with recurrent malignant glioma who were treated with bevacizumab at 5 mg / kg and irinotecan at 125 mg / m . these patients treated with a lower dose of bevacizumab showed a six - month pfs and overall survival ( os ) of 25% and 55% , respectively , with fewer thromboembolic complications .
the radiological differences in tumor enhancement pattern may be caused by several factors , among them tumor necrosis , tumor vascularity , and severity of damage to the bbb .
pope , et al . assessed the early imaging effects of bevacizumab coupled with etoposide , carboplatin , or irinotecan in a cohort of 14 patients with recurrent malignant glioma .
several patients were found to have responses in areas of necrotic - appearing tumor , whereas solid areas of their tumor continued to grow .
an explanation for this phenomenon might be found in the differences in requirements of tumor endothelium for vegf receptor stimulation in necrotic versus solid areas of tumor .
our case demonstrates two heterogeneous , synchronous gbm lesions in a patient with recurrence ; one focus displayed dense contrast enhancement while the contralateral lesion was ill - defined and nonenhancing .
following biochemotherapy with irinotecan and bevacizumab , the enhancing tumor showed dramatic resolution while the infiltrative , nonenhancing lesion progressed and ultimately lead to the demise of the patient .
this example demonstrates the heterogeneous nature of gbm and is proof of principle for antiangiogenic treatment in selected enhancing , presumably angiogenic forms of gbm , although antiangiogenic treatment may be ineffective in more infiltrative , biologically different lesions .
 glioblastoma multiforme , a neoplasm with variable histological and biological features , is characterized by diverse imaging features , including highly heterogeneous enhancement . 
 this reflects variable disruption of the blood brain barrier and inherent differences in the vascularity of the tumor . 
 experience in treating malignant glioma with antiangiogenic drugs is growing , and the most commonly used , in combination with irinotecan or other cytotoxic agents as salvage therapy , is bevacizumab , a monoclonal antibody against vascular endothelial growth factor.a 42-year - old , right - handed person with recurrent glioblastoma multiforme presented with two synchronous foci of recurrent disease in follow - up : one area with enhancement and another one nonenhancing and infiltrative , which responded differently to treatment with bevacizumab and irinotecan . 
 our example demonstrates the heterogeneous nature of glioblastoma multiforme and is proof of principle for antiangiogenic treatment in selected enhancing , presumably angiogenic forms of glioblastoma multiforme . 
 antiangiogenic treatment may be ineffective in more infiltrative , biologically different lesions . 
Introduction
Case Report
Discussion