Bevacizumab for recurrent malignant gliomas

Norden, Andrew D.; Young, Geoffrey S.; Setayesh, K.; Muzikansky, Alona; Klufas, Roman A.; Ross, Gary; Ciampa, A. S.; Ebbeling, L. G.; Levy, Brenda; Drappatz, Jan; Kesari, Santosh; Wen, Patrick Y.

doi:10.1212/01.wnl.0000304121.57857.38

Cited by 761 publications

(659 citation statements)

References 28 publications

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“…This allows the differential hypothesis of antiangiogenic therapy failing at the tumor-vascular interface, probably because of altered physiological, metabolic conditions in close proximity to the vessel. Norden et al [20] looked at 55 BEV-treated and 19 control patients. Although they did not demonstrate a difference in recurrence patterns between both groups, they concluded that there might occur a relevant discordance between the T1+c and the FLAIR appearance of the recurrent BEV-treated tumors.…”

Section: Evidence Of Increased Frequency Of Remote Relapse With Bev Tmentioning

confidence: 99%

“…It may happen that despite persistent reduction in contrast enhancement an increase in non-enhancing T2 or FLAIR signal alterations suggestive of infiltrative tumor develops [11,19,20]. This dissociation is called "discordance" between the information gathered on T1+c and T2 images [20,21].…”

Section: Introductionmentioning

confidence: 99%

“…This dissociation is called "discordance" between the information gathered on T1+c and T2 images [20,21]. Amongst others this led to a reconsideration of the Macdonald criteria [9].…”

Section: Introductionmentioning

confidence: 99%

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Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Wick

Weiler

et al. 2011

Curr Neurol Neurosci Rep

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Antiangiogenic treatment has recently become an integral part of modern cancer therapy targeting the vasculature of numerous aggressive malignancies including glioblastoma. There is preclinical evidence that antiangiogenic therapies promote glioma cell invasiveness. In clinical series, upon progression on antiangiogenic therapy with the vascular endothelial growth factor-directed antibody bevacizumab (BEV), glioblastoma has been reported to display a more infiltrative pattern of recurrence. This distant spread at recurrence or progression and a gliomatosis cerebri-like growth pattern is best detectable on fluid-attenuated inversion recovery MRI. The frequency of up to 20% to 30% of such a pattern in BEV-treated patients is higher than expected to occur without BEV. Older reports and common clinical knowledge estimate the frequency of diffuse or distant spread in recurrent glioblastoma at 10%. This observation stimulated two streams of research. One is to overcome this often insidious adverse effect of antiangiogenic treatment, to optimize antiangiogenic therapies and to face this major challenge, integrating antiangiogenic with anti-invasive mechanisms into one combined treatment concept. The second is questioning a specific property of antiangiogenic therapy to induce diffuse or distant spread. Here, alternative hypotheses of increased awareness and better imaging as well as invasiveness being part of the natural course of the disease have been tested. Without doubt, migration and invasiveness are major obstacles to successful glioma therapy, notably local therapies, both in the natural course of the disease and in the concept of "evasive resistance." However, clinical analyses of case series, matched pairs analyses, and follow-up on the BRAIN trial (A Study to Evaluate Bevacizumab Alone or in Combination with Irinotecan for Treatment of Glioblastoma Multiforme), which led to accelerated approval of BEV for recurrent glioblastoma in the United States, have not supported a specific propensity of BEV to induce diffuse growth or distant spread at recurrence.

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Section: Evidence Of Increased Frequency Of Remote Relapse With Bev Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Wick

Weiler

et al. 2011

Curr Neurol Neurosci Rep

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“…Although angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signalling pathway are efficacious, a growing body of evidence suggests that, after an initial response with vascular dropout and tumour stasis, pharmacologically impaired angiogenesis can eventually act as a detrimental driving force for enhanced tumour cell invasion into surrounding tissue, a process commonly referred to as 'evasive resistance' (Casanovas et al, 2005;Paez-Ribes et al, 2009). In clinical series, upon progression on antiangiogenic therapy with the VEGF-directed antibody bevacizumab, glioblastomas may display a more infiltrative pattern of recurrence (Norden et al, 2008b). To overcome this often insidious consequence and optimize antiangiogenic therapies, it is a major challenge integrating antiangiogenic with antiinvasive mechanisms into one combined treatment concept.…”

Section: Introductionmentioning

confidence: 99%

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

et al. 2012

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An essential mode of acquired resistance to radiotherapy (RT) appears to be promotion of tumor cell motility and invasiveness in various cancer types, including glioblastoma, a process resembling 'evasive resistance'. Hence, a logical advancement of RT would be to identify suitable complementary treatment strategies, ideally targeting cell motility. Here we report that the combination of focal RT and mammalian target of rapamycin (mTOR) inhibition using clinically relevant concentrations of temsirolimus (CCI-779) prolongs survival in a syngeneic mouse glioma model through additive cytostatic effects. In vitro, the mTOR inhibitor CCI-779 exerted marked anti-invasive effects, irrespective of the phosphatase and tensin homolog deleted on chromosome 10 status and counteracted the proinvasive effect of sublethal irradiation. Mechanistically, we identified regulator of G-protein signaling 4 (RGS4) as a novel target of mTOR inhibition and a key driver of glioblastoma invasiveness, sensitive to the anti-invasive properties of CCI-779. Notably, suppression of RGS4-dependent glioma cell invasion was signaled through both mTOR complexes, mTORC1 and mTORC2, in a concentration-dependent manner, indicating that high doses of CCI-779 may overcome tumor-cell resistance associated with the sole inhibition of mTORC1. We conclude that combined RT and mTOR inhibition is a promising therapeutic option that warrants further clinical investigation in upfront glioblastoma therapy.Oncogene advance online publication, Word Count:5,868 words Condensed title:Radiation-enhanced mTOR inhibition in glioblastomaWeiler et al. 2 AbstractA relevant mode of resistance to antiangiogenic and radiotherapy appears to be promotion of tumour cell motility and invasiveness in various cancer types, a process commonly referred to as 'evasive resistance' that may underlie progressive disease and complicates further treatment. Hence, a logical advancement in current oncology consists in optimizing antiangiogenic regimens by identifying suitable complementary strategies, ideally targeting cell motility. Here we report that clinically relevant radiation-enhanced inhibition of the mTOR complexes 1 and 2 exercises such a dual control of angiogenesis and invasiveness independent from PTEN/AKT activation in glioblastoma, a tumour entity that is paradigmatic for both excessive vascular proliferation and cell invasion. This is due to a concerted disrupture of the VEGF/VEGFR-2 signalling axis and likewise suppression of RGS4, which we identified to be a key driver of glioblastoma invasiveness. This combined antiangiogenic/antiinvasive approach might be a promising therapeutic option and warrants further clinical investigation in upfront glioblastoma therapy.Weiler et al.3

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“…27,28,32,[38][39][40][41][42][43][44][45][46][47] In addition, several retrospective studies have also been reported combining bevacizumab and irinotecan; carboplatin; carboplatin and cetuximab; carboplatin, etoposide, and ifosfamide; lomustine; carmustine; etoposide; or temozolomide. [48][49][50][51][52][53][54][55][56][57][58] Although these small studies are not easily compared due to their size and various patient populations, the consensus to date has been that no combination significantly surpasses the outcomes of bevacizumab monotherapy for recurrent glioma. 9 …”

Section: Early Study Of Bevacizumab In Patients With Recurrent Glioblmentioning

confidence: 99%

Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies

Field

Jordan

Wen

et al. 2014

Cancer

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Anti-angiogenic therapy for glioblastoma has been in the spotlight for several years, as researchers and clinicians strive to find agents with meaningful efficacy against glioblastoma. Bevacizumab in particular, in the second half of the last decade, became the most significant breakthrough in anti-glioblastoma therapy since temozolomide. Optimism for bevacizumab has been somewhat challenged given recent clinical trials that have raised questions regarding its clinical effectiveness, the optimal timing of its use and the validity of endpoints, among other issues. In addition, uncertainty has recently arisen regarding the effects of bevacizumab on quality of life and neurocognitive function, two key clinical endpoints of unquestionable significance among glioblastoma patients. In this review, we highlight these controversies and other recent work related to bevacizumab for glioblastoma. Cancer 2015;121:997

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Bevacizumab for recurrent malignant gliomas

Cited by 761 publications

References 28 publications

Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Suppression of proinvasive RGS4 by mTOR inhibition optimizes glioma treatment

Bevacizumab and glioblastoma: Scientific review, newly reported updates, and ongoing controversies

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