Avastin Patient Reviews for Malignant Metastatic Melanoma Brain Cancer

• Periodical Listing
• Neurology
• PMC3030223

Neurology. 2011 Jan 4; 76(1): 87–93.

The paradoxical effect of bevacizumab in the therapy of malignant gliomas

Received 2010 Jun three; Accustomed 2010 Aug 24.

Abstract

I rationale backside the use of agents that inhibit vascular endothelial growth gene in the therapy of primary CNS malignancies is based upon the concept that normalization of tumor vasculature with a subtract in tumor interstitial pressure level will ameliorate access of cytoreductive drugs and improve radiotherapy efficacy due to increased oxygen commitment. However, several studies have raised the concern that these agents may both rapidly restore the low permeability characteristics of the blood–encephalon barrier and counteract the benign effect of pseudoprogression. The result may be decreased therapeutic efficacy while increasing infiltration by co-opting normal vessels. In this discussion, we examine both histologic and radiographic tumor progression in the context of antiangiogenic agents. Issues dealing with the prophylactic of bevacizumab (Avastin®, Genentech, S San Francisco, CA) and its potential to decrease efficacy of standard radiochemotherapy when used to treat patients with newly diagnosed cancerous glioma are emphasized.

Bevacizumab is a recombinant humanized monoclonal immunoglobulin Thou (IgG)1 antibody that binds to vascular endothelial growth factor (VEGF) and prevents the proliferation of endothelial cells and formation of new blood vessels. ¹ VEGF has a role in endothelial cell survival, proliferation, invasion, and migration, which all affect tumor progression and angiogenesis. ^two Treatment with bevacizumab was quickly implemented for salvage therapy in progressive malignant gliomas after its efficacy was demonstrated in metastatic colon cancer ⁱⁱⁱ and in non-small-cell lung cancer. ^four Multiple groups using bevacizumab plus chemotherapy ^{2,5 ,– 12} and ii stage II trials using bevacizumab alone ^13,14 accept demonstrated impressive imaging responses with increased overall survival (OS) and progression-free survival (PFS) in recurrent glioma patients relative to historical data in patients who received chemotherapy solitary. ^xv,sixteen The results of the stage II trials were then compelling that in May 2009, the US Nutrient and Drug Administration granted approval for the employ of bevacizumab for the second-line treatment of glioblastoma multiforme (GBM). ¹⁷ Additionally, 2 recent phase 2 trials explored the use of bevacizumab plus chemotherapy as initial therapy for newly diagnosed GBM ^18,19 and several other centers are enrolling patients in 2 large phase III trials of temozolomide and radiation with and without bevacizumab for the treatment of newly diagnosed GBM. ^20,21

VESSEL NORMALIZATION

The full general rationale behind using bevacizumab in combination with chemotherapy for cancerous gliomas is twofold. First, bevacizumab normalizes vessels in the CNS past a mechanism similar to that of solid tumors outside the CNS. Bevacizumab decreases the aberrant morphology and organisation of tumor-related vasculature that causes inefficient ship of oxygen and therapeutic drugs to the tumor. ²² Every bit malignant glioma cells are known to limited VEGF, ²³ bevacizumab may have direct antitumor activity ²⁴ and may increment tumor jail cell responsiveness to the cytotoxic effects of chemotherapy that penetrates into the tumor. Secondly, bevacizumab decreases tumor interstitial pressure, which is idea to improve delivery of chemotherapy to the tumor cells. ²⁵

In preclinical studies, bevacizumab has been shown to meliorate the delivery and efficacy of systemic chemotherapeutic agents in a neuroblastoma xenograft model. ²⁶ Nonetheless, extrapolating the mechanism of bevacizumab in non-CNS solid tumors to the mechanism of bevacizumab in malignant gliomas neglects the complexities of the claret–brain barrier (BBB) compared to the vasculature of solid tumors. Using another anti-VEGF agent, vandetanib, in a malignant glioma model, Claes et al. ²⁷ demonstrated that the amount of apoptosis conferred past temozolomide (Temodar®, Schering-Turn, Kenilworth, NJ) was significantly decreased in animals that received vandetanib (Zactima™, AstraZeneca, London, UK). This led the authors to conclude that "Vessel normalization has an antagonizing rather than a synergistic or additive effect." ²⁷ Vandetanib is a tyrosine kinase inhibitor with specificity toward epidermal growth factor receptor and VEGF receptor two, ²⁸ while bevacizumab blocks signaling through VEGF receptor 1 as well as VEGF receptor 2. ¹ Given the similarities in the mechanisms of vandetanib and bevacizumab, the Claes et al. results potentially contradict the hypothesis that therapy targeting the VEGF pathway improves chemotherapy delivery to CNS tumors. In addition, the tumor phenotype changes in response to vessel normalization following treatment with bevacizumab, which may cause increased invasiveness and further resistance to antiangiogenic agents. ²⁹ Using microdialysis techniques, Portnow et al. ³⁰ demonstrated that the average maximum concentration of temozolomide in the brain compared to plasma was thirteen.6% lower than predicted by fauna models. Future studies using similar microdialysis techniques with and without bevacizumab would more definitively elucidate the potential for bevacizumab to lower tumor temozolomide concentrations.

PATTERNS OF TUMOR INVASION

There is histologic evidence that tumors may adapt to antiangiogenic agents with increased tumor invasiveness and vessel cooption. In patients, de Groot et al. ³¹ recently identified "normalized" vessels next to necrotic areas in GBM histologic specimens with tumor progression and necrosis occurring simultaneously with normalization and vessel pruning afterwards treatment with bevacizumab. These findings were besides seen in a malignant glioma model in which rats treated with bevacizumab had increased tumor with more than invasive borders than controls. ³¹

Patterns of tumor progression on MRI of patients receiving bevacizumab plus chemotherapy have likewise raised questions regarding tumor invasiveness. Zuniga et al. ³² found that xix of 38 patients had both local and distant recurrence while another 4 had just distant progression, suggesting that inhibiting angiogenesis may result in normal vessel cooption and infiltration. This same written report also showed progression on fluid-attenuated inversion recovery (FLAIR) MRI in 21 patients. Other groups have also observed significant distal progression and progression of nonenhancing tumor on FLAIR MRI. ³³ The importance of FLAIR is increasingly being recognized in response assessment in the context of widespread antiangiogenic use by such groups as the Response Assessment in Neuro-Oncology Working Grouping (RANO) ³⁴ and has been shown to be a more accurate biomarker of truthful tumor volume than postcontrast T1-weighted MRI. ³⁵ Nonenhancing tumor progression has besides been shown to exist a negative prognostic cistron independent of operation status. ³³

EFFECT OF ANTIANGIOGENESIS ON IMAGING

Bevacizumab substantially decreases contrast enhancement on T1-weighted MRI in recurrent GBM and in preclinical malignant glioma models. ^{ii,5 ,– eight,11,12,xv,36 ,– 38} Using dynamic dissimilarity enhancement (DCE) MRI at 12 T to compare the effects of bevacizumab vs high-dose dexamethasone on rat brain tumor vasculature, it was found that both dexamethasone and bevacizumab increased the time to peak enhancement compared to controls, a measure of gadolinium-based contrast amanuensis leakage into tumor. ³⁸ However, fourth dimension to peak enhancement was significantly longer when animals received bevacizumab compared to high-dose dexamethasone (figure 1). ³⁸ This suggests that the BBB stabilizing mechanisms of bevacizumab may exist more than profound than steroids. The molecular weight of the contrast amanuensis used in that written report, gadodiamide (Omniscan®, GE Healthcare, Mississauga, ON), is 574 g/mol, ³⁹ and is similar to that of SN-38 (392 g/mol), ⁴⁰ the active metabolite of irinotecan, the chemotherapeutic agent most frequently used in combination with bevacizumab to treat progressive malignant glioma. It stands to reason that if bevacizumab significantly decreases the permeability of gadodiamide, it may exercise the same for irinotecan. Using dynamic susceptibility contrast (DSC) MRI at 12 T to calculate relative cognitive blood book (rCBV) in the same malignant glioma model, a significant reduction in rCBV was demonstrated when animals were treated with bevacizumab compared to dexamethasone or controls. ^38,41 By decreasing both tumor permeability and blood volume, the mass effect of the tumor is decreased past bevacizumab even though there may be minimal or no actual antitumor effect.

Fourth dimension course for change in time to tiptop tumor enhancement

Serial dynamic contrast enhancement MRI at 12 T using gadodiamide was performed in rats with intracerebral U87 human glioma that were treated with bevacizumab or dexamethasone. Stars signal pregnant increase in fourth dimension to pinnacle enhancement. (From Varallyay et al. ³⁸ Effigy reprinted with permission.)

CLINICAL RESPONSE

The phase Two study by Friedman et al. ^thirteen showed that both irinotecan plus bevacizumab and bevacizumab alone conferred impressive Bone in patients with progressive GBM in the context of previous studies before the utilize of bevacizumab. ^15,16 The study was not powered to compare the 2 regimens head to head, so information technology is unclear if the addition of irinotecan to bevacizumab really confers a PFS or Bone benefit. Long-term follow-upward from this study demonstrated a iv-year Os of 11%. ⁴² In contrast, a cancerous glioma rat model demonstrated that the combination of bevacizumab plus carboplatin increased survival compared to either agent lone. ⁴³ This begs the question: Do some chemotherapeutic agents have a potentially synergistic effect with bevacizumab while others do not? Interestingly, all animals treated with bevacizumab in that written report lived longer but with increased tumor volume (figure 2). ⁴³ It is conceivable that a major component of bevacizumab'south efficacy is its ability to subtract tumor-related edema and blood volume thereby assuasive patients to alive longer with larger tumor volumes.

Comparison of survival and tumor volumetrics

The survival time of rats with UW28 human glioblastoma intracerebral xenografts (days afterward tumor implantation) and the histologic tumor volumes (mm³) are shown for each rat in the untreated control group (squares) and the bevacizumab (BEV) plus carboplatin (Carbo) handling group (circles). The line indicates the linear regression for each group. (From Jahnke et al. ⁴³ Figure reprinted with permission.)

Ane potentially important confounding outcome with bevacizumab is the event on inflammatory and radiochemotherapy-induced changes in GBM vasculature. The term "pseudoprogression" is used to draw the phenomenon of subacute radiochemotherapy treatment–related sequelae in CNS tumors presenting as increasing lesion book or new contrast enhancement on MRI suggestive of tumor progression. Notwithstanding, these patients often recover or stabilize spontaneously, commonly without whatever change in treatment paradigm (figure 3). ⁴⁴ The etiology of pseudoprogression is idea to be due to vascular and oligodendroglial jail cell injury, leading to inflammation and increased BBB permeability. Because the enhancement seen in pseudoprogression tin exist mistaken for actual tumor progression, patients are oft routed to bevacizumab as 2nd-line therapy for recurrence. Bevacizumab has been observed to subtract the permeability of not only tumor-related leaky vasculature but likewise of radiations-induced leaky vasculature, thereby "curing" biopsy-proven pseudoprogression. ⁴¹ This is particularly worrisome as pseudoprogression has been shown to be significantly associated with methylated MGMT promoter condition and increased survival. ⁴⁵ The presence of a methylated MGMT promoter is associated with a significant survival benefit. ^45,46 The MGMT protein removes alkyl groups from the O ⁶ position of guanine. Silencing of the MGMT promoter past methylation is clinically important because cancer cells produce less MGMT protein and cannot repair Deoxyribonucleic acid alkylation by agents such as temozolomide. ⁴⁶ Bevacizumab may decrease the correlation between MGMT status and pseudoprogression. ⁴⁵

Bevacizumab decreases enhancement of pseudoprogression

The superlative row shows series postcontrast T1-weighted MRIs using gadoteridol (T1+Gd). Dynamic susceptibility contrast with Gd or ferumoxytol (Atomic number 26) were performed before and after radiochemotherapy (RCT) and bevacizumab (BEV). Ruby-red and orange indicate increased relative cognitive blood volume (rCBV). Bevacizumab decreases T1+Gd enhancement and rCBV of both truthful progression and pseudoprogression. (From Weinstein et al. ⁴¹ Figure reprinted with permission.)

THE FUTURE OF BEVACIZUMAB IN UP-Forepart MALIGNANT GLIOMA THERAPY

Approximately 30% of patients who receive bevacizumab for recurrent malignant gliomas experience grade three and 4 toxicities. ^{x ,– 12} This is accounted tolerable in the setting of salvage therapy and spares nigh patients the undesirable side effects associated with chronic high-dose steroid use. Notwithstanding, the side furnishings of bevacizumab for the up-front treatment of GBM have not been thoroughly addressed. Standard temozolomide and conformal radiation is mostly well-tolerated. In the classic work by Stupp et al., ⁴⁷ just 7% of patients experienced grade iii or iv hematologic toxicities, 3% had severe infections, 33% had moderate to severe fatigue, 5% had thromboembolic complications, and less than 1% died from intracerebral hemorrhage. Preliminary information on the use of up-front end bevacizumab in 75 patients shows a higher rate of toxicities, including fatigue in 16%, pulmonary embolism in five%, thrombocytopenia in ten%, diarrhea in 5%, and sepsis and course 2 intracerebral hematoma in one patient each. ^xviii In a smaller study of 10 patients besides treated with upward-forepart bevacizumab, 9 patients experienced grade three and 4 events during the postradiation stage. ¹⁹ Of particular concern, 2 patients in that written report had wound breakdown. ^xix

The Radiation Oncology Therapy Grouping (RTOG) is currently enrolling 720 patients with newly diagnosed GBM in a phase III randomized controlled trial to make up one's mind if adding bevacizumab during week three of standard radiochemotherapy improves PFS and OS. ^xx The multinational AVAGLIO trial based in Europe is also a phase III trial with a similar blueprint and plans to accrue 920 patients. ²¹ In the RTOG report, progression is evaluated using standard Macdonald criteria and does not comprise the utilise of the nonenhancing tumor biomarkers FLAIR/T2 MRI as proposed past RANO. ³⁴ Because bevacizumab decreases enhancement, PFS cannot be accurately measured by the Macdonald criteria (figure 4). Only select RTOG centers volition apply DCE and DSC MRI to evaluate tumor perfusion and permeability. ²⁰ Future studies will probable increasingly contain dynamic MRI using not only gadolinium-based contrast agents (GBCA), but likewise blood pool agents such as ferumoxytol, which has demonstrated promising results in the differentiation of progression from pseudoprogression ⁴⁸ (effigy five).

Bevacizumab decreases enhancement when given up-forepart for glioblastoma multiforme (GBM)

This patient received bevacizumab before standard radiochemotherapy for newly diagnosed GBM secondary to meaning tumor volume increase and neurologic decline. (A) T1-weighted MRI before bevacizumab therapy. (B) Postcontrast T1-weighted MRI before bevacizumab therapy. (C) T1-weighted MRI three months afterward bevacizumab therapy. (D) Postcontrast T1-weighted MRI 3 months after bevacizumab therapy. Notation the substantial decrease in tumor enhancement with gadoteridol later on bevacizumab therapy (arrows) without concurrent reduction in tumor volume, mass effect, or midline shift.

Comparison of relative cerebral blood volume (rCBV) tumor progression and pseudoprogression

rCBV was obtained using both ferumoxytol and gadoteridol-based contrast agent. rCBV of 1.75 is a threshold to differentiate loftier- and low-grade gliomas. ⁵² (A) Dynamic susceptibility dissimilarity (DSC) MRI using ferumoxytol as a blood pool agent demonstrated rCBV >iv.ii in the tumor progression group (Tumor) and rCBV <one.1 in the pseudoprogression (Pseudo) group. The mixed group indicates that ferumoxytol-rCBV was high just gadoteridol-rCBV was inconsistent. (B) DSC MRI using gadoteridol demonstrated rCBV <1.seven in the 3 patients in the tumor progression group and rCBV <1.ii in the pseudoprogression group. A one-way analysis of variance was performed to evaluate the departure in rCBV values betwixt active tumor, pseudoprogression, and mixed response groups. The difference was highly statistically significant for ferumoxytol (p < 0.00001) and meaning for gadoteridol (p = 0.01). (From Gahramanov et al. ⁴⁸ Figure reprinted with permission.) These findings suggest that ferumoxytol is a more reliable agent than gadoteridol to determine rCBV in high-class gliomas.

The timing of bevacizumab administration in the RTOG 0825 study is too concerning. In 2005, Cao et al. ⁴⁹ showed that in nonenhancing tumor regions, the uptake of GBCA peaks between week iii of radiochemotherapy and 1 calendar month following the start of radiochemotherapy. This fourth dimension flow denotes the most significant BBB disruption and likely the most significant delivery of temozolomide. Thus, administering bevacizumab starting time week 3 of adjuvant radiochemotherapy will likely decrease this enhancement and potentially limit chemotherapy delivery during this therapeutic window. Although the mechanism of bevacizumab on the BBB in the CNS is not entirely clear, it is undoubtedly complex, and with an estimated monthly cost of $9,000 ⁵⁰ for 6 to 24 months, bevacizumab therapy is a serious economical issue. It should also be noted that despite the Food and Drug Administration (FDA)'s blessing of bevacizumab for the treatment of recurrent GBM, not all governing medical bodies are convinced of its efficacy for this indication. The European counterpart of the FDA, the European Medicines Bureau'southward Committee for Medicinal Products for Human being Use, rejected the awarding to change the marketing say-so of bevacizumab to include recurrent GBM lone or in combination with irinotecan in Nov 2009. ⁵¹

The purpose of this perspective is to raise bug that must be addressed prior to use of bevacizumab in newly diagnosed GBM. Clinical trials must exist designed to specifically address the following questions: 1) Does adding chemotherapy to bevacizumab upwards-front end ameliorate outcomes compared to bevacizumab alone? ii) Does BBB stabilization by bevacizumab increase chemotherapy delivery or really decrease chemotherapy commitment to CNS tumors? 3) If bevacizumab has the potential to subtract chemotherapeutic commitment, would administering chemotherapy before bevacizumab help negate this outcome? The timing of bevacizumab in relation to other therapeutic modalities (radiations and chemotherapy) will be highly dependent on the actual machinery of bevacizumab in tumor vasculature. iv) What exercise we utilise to relieve our patients receiving up-front end bevacizumab at recurrence? Information technology is important to respond these questions when bevacizumab has the potential to paradoxically decrease temozolomide delivery and prevent pseudoprogression, both of which may bear upon survival.

Footnotes

BBB

blood–brain barrier

DCE

dynamic contrast enhancement

DSC

dynamic susceptibility dissimilarity

FDA

Food and Drug Administration

FLAIR

fluid-adulterate inversion recovery

GBCA

gadolinium-based contrast agent

GBM

glioblastoma multiforme

IgG

immunoglobulin G

OS

overall survival

PFS

progression-gratis survival

RANO

Response Assessment in Neuro-Oncology Working Group

rCBV

relative cerebral claret volume

RTOG

Radiation Oncology Therapy Group

VEGF

vascular endothelial growth factor

DISCLOSURE

Dr. Thompson reports no disclosures. Dr. Frenkel serves as an Acquaintance Editor for Clinical and Applied Thrombosis/Hemostasis; may accrue revenue on a patent re: Synergistic interaction of cyclic histone deactylase inhibitor with EGFR targeted drugs; and serves every bit a consultant for Shionogi & Co., Ltd. Dr. Neuwelt receives research back up from the NIH and from the Us Section of Veterans Affairs.

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