A narrative review of therapeutic targeting of angiogenic signalling pathways: VEGF and bevacizumab in cancer

Introduction

Background and rationale

Angiogenesis is an important process that occurs throughout life, where new blood vessels are formed from pre-existing ones. In utero, generation of new blood vessels is essential for foetal development. In adults, angiogenesis does not need to occur as often, only in a few situations is it necessary, for example during wound healing and the female ovarian cycle (1). However, if angiogenesis diverts from its quiescent state in adulthood it can conttribute to the pathogenesis of different diseases such as rheumatoid arthritis, retinopathies and cancer (2).

Various drugs have been developed to target such processes, including Bevacizumab, which was one of the first angiogenesis inhibiting drugs to be approved as a therapeutic drug (3).

Objectives

The objective of this narrative review is to provide an overview of the mechanism of angiogenesis and highlight the involvement of various molecular pathways in this process, focusing on a particularly important angiogenic factor, vascular endothelial growth factor (VEGF), and its targeting for the treatment of cancer. Additionally, there is a focus on assessing the efficacy of bevacizumab in the treatment of various cancers. An overview of the key studies reporting benefit of adding bevacizumab to treatment versus a placebo or compared to another drug is provided. The review of clinical trials also briefly examines the adverse effects of this drug, thus investigating the limitations of such therapy. We present this article in accordance with the Narrative Review reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-24-98/rc).

Methods

A literature search was carried out on 1 June 2024 using PubMed search engine using search strategy mentioned in Table 1.

The inclusion criteria included papers available on PubMed and written in English. All trials investigating bevacizumab versus a control with outcomes looking at the efficacy of bevacizumab compared to a placebo or existing treatment in cancer were retrieved. There was no limitation put on the date the paper was written (Table 1). All trials reporting efficacy of bevacizumab as approved treatment for different type of cancer were included.

The angiogenic switch

Both pro- and anti-angiogenic factors, which can activate and inhibit angiogenesis respectively, are produced by cells in the body. The balance between these activators and inhibitors will determine the angiogenic activity of blood vessels. Therefore, in adults where angiogenesis is mainly quiescent, there must remain a homeostasis between the factors. If the balance changes in favour of the pro-angiogenic factors, it leads to an ‘angiogenic switch’ and can lead to disease progression, if angiogenesis is not needed in that situation (4) (Figure 1).

Figure 1 Drawing showing the balance between inhibitors and activators of angiogenesis that must be kept in the body. Here there is an imbalance which can result in neovascularisation. EGF, epidermal growth factor; FGFs, fibroblast growth factors; LPA, lysophosphatic acid; PDGF, platelet-derived growth factor; VEGFs, vascular endothelial growth factors.

The change in angiogenic factor balance can be influenced by hypoxia or genetic alterations in the cells (5). Hypoxia is an important factor in the angiogenic switch, especially in tumours. As the tumour grows, conditions can become hypoxic and there is an increased need for improved perfusion. Hypoxic stress can lead to the secretion of hypoxia-induced factor (HIF) (6). In these conditions, the subtypes HIF-1α and HIF-2α will dimerise and translocate to the cell nucleus. The heterodimer will bind the hypoxia-response element (HRE) DNA sequence which is a promoter region of the gene transcribing various genes, including that of VEGF. Therefore, an increase in HIF will lead to an increase in VEGF, a major pro-angiogenic factor, leading to an angiogenic imbalance (7). HIF levels can also be controlled by oxygen-independent factors, such as gene alterations. One example of this is the mutation of the Von Hippel-Lindau (VHL) tumour suppressor gene, which transcribes the VHL protein (pVHL). pVHL favours the degradation of HIF in normoxia, by promoting the binding of ubiquitin to HIF-1α which has already been hydroxylated by HIF-prolyl hydroxylase. The bound ubiquitin is detected by the proteasome, leading to the HIF degradation. Therefore, mutations in the VHL gene can lead to a decrease in pVHL, consequently leading to an increase in HIF, and thus VEGF, in normal oxygen levels (6).

The presence of HIF is just one example of a factor that can induce the angiogenic switch. Mutations in oncogenes, for example, the Ras oncogene, or tumour suppression genes, can lead to increased expression of pro-angiogenic factors (4). This increased expression can then lead to pathological angiogenesis and allow progression of disease (Figure 2).

Figure 2 Flow diagram to describe the process of ‘sprouting angiogenesis’. ECM, extracellular matrix.

The process of angiogenesis

The formation of new blood vessels is a complex and dynamic process. In embryonic development, de novo endothelial production occurs from bone-marrow progenitor cells, in a process called vasculogenesis (8). A vascular network can then develop from this by different types of angiogenesis, such as sprouting or intussusceptive angiogenesis; these processes also occur in adults (Figure 3) (9).

Figure 3 Diagrams to show the differences between the processes of (A) sprouting angiogenesis, (B) vasculogenesis and (C) intussusceptive angiogenesis.

Sprouting angiogenesis is characterised by the sprouting of new vessels, forming from a pre-existing vessel. Intussusception is also called splitting angiogenesis, where new daughter vessels develop where a vessel already exists. It is a less-understood process in comparison to sprouting angiogenesis (9).

Diversity of angiogenesis

Angiogenesis requires a variety of factors and proteins for the complex process to occur. Table 2 outlines signalling molecules and their receptors present in each step shown in Figure 2. This is not an extensive list as it only highlights some of the main molecules involved. Furthermore, molecules can interact with one another or cause the production of other factors, for example matrix metalloproteinases (MMPs) are used to degrade the extracellular matrix but they can also aid in the detachment of pericytes from the vessel by releasing angiogenic factors from the extracellular matrix (ECM) which are involved in this process (10).

VEGF

VEGF family

VEGF is an essential pro-angiogenic factor, both in adults and in foetal development. If the VEGF gene is deleted, the embryo cannot develop and survive, having lethal consequences (11). In humans, the VEGF family includes: VEGFA, VEGFB, VEGFC, VEGFD, VEGFE and placental growth factor (PLGF). PLGF also has four human isoforms: PLGF1–4 (12). The VEGF receptors, VEGFR1 (also named Flt-1), VEGFR2 (Flk-1/KDR) and VEGFR3 (Flt-4), are tyrosine kinase receptors (12). VEGFR3 (Flt-4) only binds to VEGFC and VEGFD, which are involved in lymphatic angiogenesis rather than that of blood vessels. There are also two non-tyrosine kinase receptors, neuropilins (NRP1 and 2). These can act as co-receptors to the VEGFRs or they can bind to some VEGF isoforms and are involved in functions such as vascular maturation (11,12).

VEGFA function and mechanism

Of the VEGF family, VEGFA is the most well-known and studied. It binds to both VEGFR1 and VEGFR2, however, VEGFR2 is recognised to be the main receptor to which VEGFA binds in order to have its angiogenic effects. The importance of VEGFR2 can be demonstrated when mice with the gene coding for this receptor were knocked out and embryos could not develop vessels, leading to embryonic death in utero between days 8.5–9.5 of development (13).

When the VEGFA ligand binds to the VEGFR2 receptor, it leads to receptor dimerization which consequently leads to conformational changes of the transmembrane helices and the intracellular regions of the receptor. This results in kinase activation and autophosphorylation of the tyrosine. Cytoplasmic signalling proteins can then bind with the phosphorylated receptor, which can then initiate pathways that result in various effects seen by VEGFA. For example, it can lead to the phosphorylation and activation of PLC-γ, which catalyses the splitting of phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-triphosphate (IP₃) and diacylglycerol (DAG). Firstly, DAG can activate protein kinase C (PKC), which in turn leads to the protein kinase cascade that results in ERK 1/2 (extracellular signal-regulated kinase) phosphorylation. Activation of ERK can alter transcription factors and thus gene expression, leading to endothelial cell proliferation. Secondly, IP₃ can increase intracellular calcium levels, triggering the synthesis and release of nitric oxide by endothelial nitric oxide synthase (eNOS). This leads to vasodilation and increased permeability of the vessel wall, which is seen in the early stages of angiogenesis (14,15).

Other VEGF mechanisms

Apart from its role in angiogenesis, VEGF is a survival factor. One mechanism by which this happens is through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. When VEGFR2 is phosphorylated by the binding to VEGFA, it can activate PI3K and then, downstream, the Akt signalling enzyme is activated (16). Akt then phosphorylates proteins that are involved in the cell’s apoptotic mechanisms, such as BAD (a pro-apoptotic factor) and Caspase 9 (a protease). This phosphorylation renders the protein inactive, thus suppressing its apoptotic effect (17).

Not only does VEGF have its own effects and molecular pathways in the cell. It can influence other factors and pathways, one example of this is the DLL4/NOTCH signalling pathway. VEGFA can induce the production of DLL4 (delta-like protein) in tip cells. This is important in the process of differentiation of cells into tip cells and stalk cells. The DLL4 will activate its receptor (NOTCH) in neighbouring cells, which in turn will suppress the presence VEGFR2 in these cells, the stalk cells. Therefore, the stalk cells will not be attracted to and move towards the VEGFA stimulus, which the tip cells do. This means that endothelial cells that are more exposed to VEGFA will more likely become tip cells and their neighbours induced into stalk cells (9).

VEGF is essential for the survival and growth of cells. However, if VEGF levels are too high, it can lead to pathologies involving neovascularisation, such as tumour progression. Therefore, the maintenance of VEGF concentrations within a non-pathological range is of utmost importance.

Dangers of neovascularisation

Angiogenesis is a normal physiological process, so how can this become pathological? This varies from disease to disease, however, he main idea is that the new vessels formed in neovascularisation are not as stabilised as normal vessels, for example, due to insufficient pericyte recruitment in the vessel maturation stage (4).

Atherosclerosis is an example of a disorder in which neovascularisation plays a role. Within the plaque, angiogenesis occurs to increase the supply of oxygen and nutrients as it grows in size. The new vessels in the plaque will lead to instability. One risk is the occurrence of an intraplaque haemorrhage since the vessels will have an increased permeability and be leaky, thus leading to erythrocyte extravasation in the plaque. Plaque instability is dangerous as it can lead to a rupture and, consequently, a thromboembolic event (18).

Another important disease in which neovascularisation contributes to its pathology is tumours. Not only does development of new vessels allow for growth of the tumour, but it also increases the risk of metastasis in the body as tumour cells can break off into the new vessels and spread through the blood supply. Furthermore, there is also the increased risk of intra-tumoral ruptures or haemorrhages similar to in atherosclerotic plaques (4).

The dangers of neovascularisation mentioned are only a few from an extensive list, thus supporting the interest in targeting neovascularisation in the treatment of such diseases.

Therapeutic targeting of VEGF in tumours

The pro-angiogenic power of VEGF makes it a desirable target for tackling the problem that neovascularisation poses with tumour progression.

The imbalance in the expression of VEGF can have various origins. As mentioned before, hypoxia leading to the production of HIF or mutations in the VHL tumour suppressor gene can increase VEGF. Other oncogenes that have also been found to lead to VEGF overexpression include Ras, HER2 and BCR-ABL genes (11).

Not all tumours will respond to VEGF targeting in the same way. This will depend on their angiogenic mechanism and the importance that VEGF may or may not have in it. For example, renal cell carcinoma (RCC) shows a high reliance on VEGF as it significantly inactivates the VHL gene. So, VEGF therapy proves to be more effective with RCC than with some other tumours where VEGF targeting has little or no clinical benefit (19).

Another cancer in which it is known that VEGF is implicated is colorectal cancer (CRC). VEGF has been seen to have a role in its metastatic spread as it infiltrates the lymphatic system. As such, it has been identified that there is a correlation between VEGF expression in CRC and their prognosis (20).

VEGF therapy drugs can target different aspects of the VEGF pathway, including the VEGF molecule itself (e.g., bevacizumab), the VEGF receptor (e.g., ramucirumab) or the intracellular molecular signalling pathways such as the Ras/Raf/MAPK pathway (e.g., sorafenib) (21).

Table 3 summarises the key concepts in therapeutic targeting of VEGF in tumours.

Adverse effects of VEGF targeting

With the targeting of VEGF pathway, there are adverse effects that can come with the treatment, a major one being hypertension. Hypertension is seen as VEGF contributes to the production of endothelium-derived relaxing factors (EDRFs), such as nitric oxide. Therefore, blocking VEGF can lead to reduced production of EDRFs and thus vasoconstriction (22). However, this is dose-dependent, as shown by a phase II study with bevacizumab used to treat RCC. Occurrence of serious hypertension was shown to be greater in the high-dose group in comparison to the low-dose group. Of the 39 patients in the high-dose group, 14 were hypertensive; of the 37 patients in the low-dose group, 1 had hypertension. Hypertension then decreased with cessation of the drug therapy (23).

Other adverse effects of VEGF targeting include proteinuria, arterial thromboembolic events, cardiomyopathy, haemorrhage, and wound implications, such as impaired or delayed healing (22).

Another concern with anti-VEGF therapy is the development of resistance (Table 4). This can occur as, when the VEGF pathway is inhibited, the production of other angiogenic factors, e.g., FGF and ANG-1, can be induced. Pre-clinical models have shown that FGF, ANG-1 and Ephrin production increased when VEGFR2 inhibitors were used to treat pancreatic cancers (21). One method to overcome this issue of resistance would be to trial VEGF-therapy drugs in conjunction with other drugs that target other pathways, such as FGF (Table 5) (24).

Tumour cells have also been shown to develop mechanisms in order to escape angiogenic inhibition; for example, vessel co-option, where the tumour incorporates the body’s own vessels from surrounding tissues instead of creating completely new vessels, and vasculogenic mimicry, whereby tumour cells mimic endothelial cells to create their own vascular network (21).

Although there are risks that come with the therapeutic targeting of the VEGF pathway, in some cases, the benefits outweigh the drawbacks and some drugs have been approved for use in certain tumours.

Bevacizumab

Bevacizumab remains the most commonly used anti-angiogenic drug for cancer treatment that has been extensively trialled. It is a humanised monoclonal antibody that targets all circulating isoforms of VEGFA leading to the prevention of VEGFA binding VEGFR-2 (3).

Since its first approval as a therapeutic drug in metastatic CRC, it has been approved for use in combination with other chemotherapy agents in other tumour types such as metastatic RCC, non-small cell lung cancer (NSCLC), ovarian cancer, cervical cancer (CC), glioblastoma (GB), and hepatocellular carcinoma (3,25).

Table 6 summarises the current pharmacological information about bevacizumab.

Clinical trials of bevacizumab

Metastatic CRC

The first phase III trial, published in 2004, for the use of bevacizumab as a first-line treatment was a randomised controlled trial consisting of 813 patients with untreated metastatic colorectal cancer (mCRC) (26). Patients were randomised into two groups: 402 patients in the treatment group receiving 5 mg/kg bevacizumab and chemotherapy (IFL: irinotecan, fluorouracil and leucovorin), and 411 patients in the control group receiving IFL with a placebo. There was a significant improvement in their primary endpoint, overall survival duration. Median duration of survival in the control group was 15.6 and 20.3 months in the treatment group, with a hazard ratio of death being 0.66. There were also improvements seen in their secondary endpoint parameters, such as progression-free survival duration (10.6 vs. 6.2 months in treatment vs. control groups) and overall response rate (34.8% vs. 44.8% in treatment vs. control).

One issue that was seen was a 10% increase in the occurrence of grade 3 or 4 adverse events in the treatment group compared to the control group, such as hypertension and proteinuria. However, only a small percentage of these events lead to discontinuation of treatment or death.

This study was a well-laid-out trial, with consistency in baseline characteristics maintained in both groups, reducing bias. A point to raise would be the fact that, of all the patients in the study, 60% were male and 80% were of white ethnicity. This may be a misrepresentation of the global population. Regardless, this study, overall, was a success. Although the occurrence of adverse events was significantly improved in the treatment group, the fact that, in most cases, they were treatable means that the efficacy of the drug in the treatment of the cancer outweighs this drawback.

This trial led to the approval of bevacizumab for use as a first-line treatment for mCRC, making it the first anti-angiogenic drug to be approved for therapeutic use. It is now the standard-of-care treatment for mCRC (3).

Further trials have been undertaken to show the efficacy of bevacizumab in the treatment of mCRC alongside different chemotherapy treatments (3). These trials report benefit of bevacizumab in combination with newer chemotherapy regimens [fluorouracil/leucovorin or capecitabine/oxaliplatin (XELOX)] in the first-line setting (AVF0780g and NO16966) and in combination with leucovorin/fluorouracil and oxaliplatin (FOLFOX) in the second-line setting (E3200), as well as the persistent benefit with bevacizumab treatment in multiple lines (ML18147) (27-30).

A more recent study, in 2023, was carried out to determine the efficacy of combination therapy with trifluridine-tipiracil (FTD-TPI) and bevacizumab in the treatment of refractory mCRC (31). Patients in the study had to have received a maximum of two previous chemotherapy regimens with no improvement in disease state, either the disease continued to progress, or patients experienced serious adverse effects, so they had to discontinue treatment. Patients were randomly allocated to have FTD-TPI plus bevacizumab (treatment group) or to have FTD-TPI treatment alone (control group) in 28-day cycles.

A total of 246 patients were allocated to each group. However, in the treatment group and in the control group, only 32 and 4 patients, respectively, received treatment for the time frame of the full trial. Patients did not complete the trial if there was disease progression (either observed radiologically or clinically) or patients experienced serious adverse events.

Overall, there was an improvement in overall survival, the primary end point. The median overall survival was 10.8 and 7.5 months in the treatment group and the control group, respectively, with a hazard ratio for death of 0.61.

The secondary end point of progression-free survival saw an improvement, being 5.6 months in the treatment group compared to 2.4 months in the control group.

Adverse events were also studied, however, both groups had the same number of patients (16 patients in each group) to discontinue the trial treatment due to serious adverse events. A proportion of 72.4% of patients in the treatment group reported adverse events of grade 3 or above compared to 69.5% in the control group. However, there were no adverse events that caused death reported.

This trial was not a double-blinded study as FTP TDI was an oral administration and the bevacizumab was given as an intravenous (IV) dose. The patients were generally randomised fairly, according to their demographics, and are seen to be representative of the general target population. However, it should be noted that the majority of patients (88.4%) were of White ethnicity, due to inability to recruit other ethnicities to take part in the trial.

The trial found that the treatment did benefit in achieving a longer median overall survival time, however, a limitation was that a very small proportion of both groups fully completed the trial.

As with the first clinical trial mentioned previously, the occurrence of adverse events was significant, however, these were treated, and there was no mortality from these events.

Since its ratification over a decade ago, bevacizumab remains a standard-of-care therapy in mCRC, recommended in conjunction with chemotherapy for induction and as maintenance treatment (32,33).

Metastatic RCC

Bevacizumab was the first anti-angiogenic treatment to show clinical effectiveness in advanced RCC. The key study AVOREN demonstrated a reduction in the risk of disease progression (secondary endpoint) by 37% [hazard ratio (HR): 0.63, P=0.0001] with the addition of bevacizumab to interferon alpha (INF-α) 2b compared to INF-α 2b alone (34). However, the therapy did not offer an overall survival benefit (primary endpoint) (35). Based on these results, bevacizumab was endorsed as the first-line for treatment of RCC in the first-line setting in combination with INF-α 2b. The results from AVOREN were confirmed in the subsequent CALGB 902065 study (36).

The phase III CALGB 902065 trial enrolled 732 patients, with 363 randomised to receive INF-α only (control group) and 369 in the INF-α and bevacizumab group (treatment group). The primary end point was overall survival, which showed an improvement in the treatment group, 18.3 months, compared to 17.4 months in the control group.

NSCLC

Bevacizumab was among the first targeted therapies available for NSCLC and the first drug to improve survival beyond one year when combined with chemotherapy. Approval as first-line therapy was based on results of the pivotal study E4599 which demonstrated a reduction in the risk of death by 21% (HR: 0.79, P=0.003) with the addition of bevacizumab to carboplatin plus paclitaxel compared to carboplatin plus paclitaxel alone and an improvement in median overall survival from 10.3 to 12.3 months (37).

The AVAiL phase III trial was carried out to investigate the efficacy of adding bevacizumab to cisplatin and gemcitabine (CG) in the treatment of non-squamous NSCLC (38). There were three arms in this study, as they also trialled with two different doses of bevacizumab. A total of 1,043 patients were randomly assigned by centralised stratification into three groups: CG with placebo (347 patients), CG plus low-dose bevacizumab (345 patients), and CG plus high-dose bevacizumab (351 patients).

Patients were then given the chemotherapy on a three-weekly basis and continued for up to six cycles. After the six cycles, if completed, the patients could continue with monotherapy of either the placebo or bevacizumab that they were assigned.

Primary end point was unstratified progression-free survival, in which there was an improvement displayed in the treatment arms compared to the control. Median progression-free survival was 6.7, 6.5 and 6.1 in the low-dose bevacizumab, high-dose bevacizumab, and the control groups, respectively.

Secondary end points were objective response rate, duration of response and overall survival. All of which saw improvements in the treatment groups in comparison to the control group.

Adverse events were seen in all three groups, however, events of grade 3 or higher were seen more in the high-dose bevacizumab group. There were deaths associated with adverse events in all three groups: 4%, 4% and 5% in the control, low-dose bevacizumab, and high-dose bevacizumab arms, respectively.

This study was carried out worldwide, with participating centres in Europe, Eastern Asia, Australia, Central and South America, and Canada. Although a wide range of countries, the results were relatively consistent across all centres. However, one thing to note would be that the study population had more favourable characteristics in terms of prognosis, for example, patients were younger, and exclusion of patients with tumours invading major blood vessels.

This trial demonstrated a benefit of using bevacizumab as an adjuvant to cisplatin-gemcitabine chemotherapy in non-squamous NSCLC. Although the improvement was by a small margin compared to the placebo, these are still significant results and corroborate the results from previous clinical trials that demonstrate benefit to using bevacizumab in the same situation (39,40). It is interesting that the high-dose bevacizumab displayed a similar, if not lower, median progression-free survival in comparison to the low-dose bevacizumab. However, this study was not set up to analyse such results as the main aim of the trial was to compare the placebo to the treatment.

Despite significant evolution in the therapeutic landscape for NSCLC, bevacizumab continues to feature as a therapeutic strategy in combinations with other targeted therapies such as erlotinib and atezolizumab (41-44).

Ovarian cancer

Bevacizumab was approved as the first targeted therapy for treatment of advanced ovarian cancer in the front-line setting following the publication of results from the key study GOG-0218, which reported a significant increase in median progression-free survival from 10.3 to 14.1 months with the addition of bevacizumab to chemotherapy (45). Although in GOG-0218 there was no significant difference in overall survival between treatment arms in the overall population, in the subgroup of patients with stage IV disease, bevacizumab used in combination with chemotherapy followed by maintenance treatment demonstrated an improvement in overall survival compared to chemotherapy alone (median overall survival 42.8 vs. 32.6 months, HR: 0.75) (46). The effectiveness of bevacizumab in the front-line setting was validated by ICON7 (47), and additional key phase 3 clinical trials in the platinum-sensitive (OCEANS and GOG-0213) (48,49) and platinum-resistant (AURELIA) (50) scenarios led to its acceptance in the recurrent setting. Recently published trials of bevacizumab in combination with olaparib (51) and olaparib with durvalumab (52,53) report improved progression free survival and overall survival.

Although the therapeutic landscape has changed substantially in the last decade, bevacizumab remains an important standard of care and the only approved anti-angiogenic agent for treatment of ovarian cancer.

CC

Bevacizumab emerged as the first notable advance in many years in the treatment of persistent or recurrent CC, filling a substantial treatment gap and setting the global standard for patients with CC.

GOG240 was the pivotal study that led to the approval of bevacizumab (54). This trial was carried out to investigate the effect of adding bevacizumab to non-platinum chemotherapy in the management of recurrent, persistent, or metastatic CC. There were two types of chemotherapy combinations that patients would be given: either cisplatin plus paclitaxel or topotecan. Patients receiving either would then also be administered a placebo or bevacizumab. A total of 452 patients were randomised into the four treatment groups: cisplatin plus paclitaxel only (114 patients), topotecan plus paclitaxel only (111 patients), cisplatin plus paclitaxel with bevacizumab (115 patients), and topotecan plus paclitaxel with bevacizumab (112 patients). However, these populations could be grouped as either the chemotherapy only group, the control, or the chemotherapy plus bevacizumab group, as the treatment group.

One primary end point of the study was overall survival, in which there was an improvement seen in the treatment group. The median overall survival was 13.3 and 17.0 months in the control and the treatment groups, respectively. Although patients within each of these groups were receiving two different chemotherapy agents, there was no finding of a change in overall survival depending on whether the patient was receiving cisplatin compared to topotecan. Furthermore, there was no increase in mortality, nor any benefit or disadvantage associated with receiving either chemotherapy agent over the other.

Another primary end point analysed was the occurrence of adverse events, noting their frequency and severity. There was an associated increase in the occurrence of adverse events in the treatment group, including hypertension of grade 2 or above (25% compared to 2% in the control, thromboembolic events of grade 3 or above (8% compared to 1%), and gastrointestinal fistulae of grade 3 or above (3% compared to 0%). Other events, such as non-febrile and febrile neutropenia, pain and proteinuria had no difference between the groups. With regards to severity, fatal events occurred in 1.8% of patients in both groups.

This trial demonstrated an improvement in the overall survival in patients receiving bevacizumab in addition to chemotherapy in the treatment of CC (55). However, this was associated with increased adverse events, therefore risk must be weighed aginst benefit. Although patients were receiving different chemotherapy regimens, this was considered during analysis and was found not to have a significant impact on the efficacy of the trial, so it worked as a suitable control.

A recently published subgroup analysis of KEYNOTE-826 reported that adding pembrolizumab to chemotherapy with or without bevacizumab improved overall survival across subgroups of patients with persistent, recurrent, or metastatic CC (56). The BEATcc trial (ENGOT-Cx10-GEICO 68-C-JGOG1084-GOG-3030) evaluated the addition of an immune checkpoint inhibitor (atezolizumab) to bevacizumab and reported significantly improved progression-free and overall survival, substantiating the role of bevacizumab as the standard backbone for metastatic, persistent, or recurrent CC (57).

Hepatocellular carcinoma

Bevacizumab showed response rates of 13% to 14% in single-agent phase II studies in patients with advanced liver cancer (58,59). A phase Ib study of check point inhibitor atezolizumab plus bevacizumab, as a strategy of augmented antitumour activity, in patients with untreated unresectable hepatocellular carcinoma showed a tolerable side-effect profile and encouraging antineoplastic activity, with an objective response rate of 36% and a median progression-free survival of 7 months (60).

IMbrave150, a phase III trial, was carried out to compare the benefits of adding bevacizumab versus sorafenib, a multikinase inhibitor, to atezolizumab in the treatment of unresectable hepatocellular carcinoma (61). Sorafenib was already being used as a first-line treatment for such cancers, so this trial wanted to see if bevacizumab would prove to be more effective in increasing survival in comparison.

A total of 501 patients were assigned to the groups in a 2:1 ratio, with 336 patients receiving atezolizumab plus bevacizumab and 165 patients receiving atezolizumab plus sorafenib. The treatment was continued until toxic adverse events occurred or until there was no longer any clinical benefit observed in the patient.

Primary end points of this trial were overall survival and progression-free survival, both of which saw an increase in the bevacizumab group compared to the sorafenib group. Estimated rates of survival was 84.8% at 6 months and 67.2% at 12 months in the bevacizumab group, compared to 72.2% and 54.6% at 6 and 12 months in the sorafenib group. In the bevacizumab group, the median progression-free survival period was 6.8 months, compared to 4.3 months with sorafenib. Furthermore, progression-free survival at 6 months was 54.5% with bevacizumab, compared to 37.2% with sorafenib. These results were seen to be statistically significant.

Secondary end points were objective response rate and duration of response, both of which were improved in the bevacizumab group. Objective response rate was 27.3% and 11.9% in bevacizumab and sorafenib groups, respectively. The estimated percentage of patients with a duration of response longer than 6 months was 87.6% and 59.1% in bevacizumab and sorafenib groups, respectively.

Occurrence of adverse events was observed and recorded, noting frequency and severity. In both groups, there was a high percentage of patients who experienced adverse events, of any severity or grading, 98.2% with bevacizumab and 98.7% with sorafenib. However, more serious adverse events (grade 3 or above) occurred more with bevacizumab, 38.0% compared to 30.8% with sorafenib. The most common serious adverse event was hypertension, which was expected. 15.5% and 10.3% in the bevacizumab and sorafenib groups, respectively, discontinued treatment due to adverse events.

This trial has some caveats, for example, the patients were not blinded as administration of the drugs did not allow this since sorafenib is an oral agent and bevacizumab is an intravenous agent. Furthermore, the patients were not assigned in an equal proportion to each treatment group.

However, regardless of these points, the study still showed that bevacizumab has a benefit and has the potential to have a role in the management of unresectable hepatocellular carcinoma.

GB

Bevacizumab has shown unparalleled response rates in this difficult-to-treat disease. The key study AVF3708g in relapsed or progressing GB demonstrated progression free survival benefits compared to historic controls in recurrent GB. Bevacizumab as a single agent resulted in a median progression free survival of 4.2 months while in combination with irinotecan that increased to 5.6 months (62). These results led to approval of bevacizumab for treatment of relapsed or progressing GB in the United States and other countries. Thereafter, the phase III study EORTC 26101 verified the progression free survival benefit, reporting a reduction in the risk of disease progression (secondary endpoint) by 51% (HR: 0.49, P<0.0001) with the addition of bevacizumab to lomustine compared to lomustine alone (63). However, the observed progression free survival benefits did not translate into an overall survival benefit in AVF3708g or EORTC 26101. However, indirect evidence from epidemiologic data, from cancer registry, suggested a positive impact of bevacizumab on overall survival in patients with GBM (64).

The important study AvaGlio/BO21990 analysed the impact of addition of bevacizumab to radiotherapy and temozolomide compared to radiotherapy and temozolomide alone in patients with GBM. The trial reported a reduction in the risk of disease progression (co-primary endpoint) by 36% (HR: 0.64, P<0.0001) with the addition of bevacizumab, though this did not translate into improved overall survival (co-primary endpoint) (65). RTOG0825 study reported similar results (66). These studies firmly established the status of bevacizumab as the first pharmacologic agent for patients with GBM, demonstrating unequivocal evidence of a longer maintenance of quality of life and performance status (65,66).

In the AvaGlio/BO21990 study, an additional benefit of bevacizumab therapy was the reduction in glucocorticoid requirements, which are the mainstay of treatment for brain oedema in patients with GB. However, glucocorticoids are associated with significant morbidity due to well-recognised serious adverse effects. In the bevacizumab group, a greater proportion of patients who were receiving glucocorticoids at baseline were able to terminate glucocorticoids compared to radiotherapy and temozolomide alone (66.3% vs. 47.1%), and the time to commencement of glucocorticoids was longer in patients who were not prescribed glucocorticoids at baseline (12.3 vs. 3.7 months) (65). Currently, bevacizumab continues to be the only approved and preferred anti-angiogenic agent and targeted therapy in GB.

Table 7 summarises pivotal studies of bevacizumab usage in cancer.

Strengths and limitations of this narrative review

This narrative review has various strengths, firstly, the literature review is well-rounded, and we have been able to give a detailed description of angiogenesis and its mechanisms of action before its application in a clinical setting. The papers selected to review the use of bevacizumab in treatment of cancer were selected as they were pivotal studies with large numbers and robust conduct. They all had the same objectives: to investigate the efficacy of addition of bevacizumab to the treatment of the cancer. Finally, the papers together all had similar end points; therefore, a trend can be identified and compared to each other.

However, this review has limitations inherent in all narrative reviews, including a lack of rigorous systematic search for evidence, difficulty in critically appraising against strict criteria, and selection bias.

Conclusions

Angiogenesis is an essential physiological process for life. However, it must be kept at a certain balance, or else can have detrimental effects. The diversity and complex nature of its mechanism make it increasingly difficult to tackle, however, pinpointing major pathways has proven to be successful in some cases.

The targeting of VEGF has had a great impact in the treatment of various cancers, as shown by many different clinical trials that have been carried out over the years. These have led to the approval of the use of bevacizumab in a variety of different cancers, even as first-line treatment in some cases. However, it is not applicable to all cancers, and its efficacy varies. Furthermore, the occurrence of adverse events and risks that the agent provides should be considered and must be weighed against the benefits of its use. Although this is the case, it has shown the potential that the therapeutic targeting of angiogenesis holds. This has led to the production of more anti-angiogenic drugs in the treatment of cancers and other neovascular pathologies.

The ability of tumour cells to evolve and avoid anti-angiogenic agents, primarily due to resistance and the evasion mechanisms, opens further avenues for research to tackle these complex obstacles and is currently being investigated in a number of trials.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-24-98/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-24-98/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-24-98/coif). S.G.R. serves as an unpaid editorial board member of AME Medical Journal from April 2024 to December 2024 and serves as an unpaid Associate Editor-in-Chief of AME Medical Journal from January 2025 to December 2026. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol 2002;282:C947-70. [Crossref] [PubMed]
2. Khurana R, Simons M, Martin JF, et al. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation 2005;112:1813-24. [Crossref] [PubMed]
3. Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020;86:102017. [Crossref] [PubMed]
4. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer 2003;3:401-10. [Crossref] [PubMed]
5. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 2020;77:1745-70. [Crossref] [PubMed]
6. Hashimoto T, Shibasaki F. Hypoxia-inducible factor as an angiogenic master switch. Front Pediatr 2015;3:33. [Crossref] [PubMed]
7. Dengler VL, Galbraith M, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol 2014;49:1-15. [Crossref] [PubMed]
8. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 2011;473:298-307. [Crossref] [PubMed]
9. Carmeliet P. Angiogenesis in health and disease. Nat Med 2003;9:653-60. [Crossref] [PubMed]
10. Rundhaug JE. Matrix metalloproteinases and angiogenesis. J Cell Mol Med 2005;9:267-85. [Crossref] [PubMed]
11. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967-74. [Crossref] [PubMed]
12. Holmes DI, Zachary I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 2005;6:209. [Crossref] [PubMed]
13. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62-6. [Crossref] [PubMed]
14. Peach CJ, Mignone VW, Arruda MA, et al. Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. Int J Mol Sci 2018;19:1264. [Crossref] [PubMed]
15. Matsumoto T, Claesson-Welsh L. VEGF receptor signal transduction. Sci STKE 2001;2001:re21. [Crossref] [PubMed]
16. Ruan GX, Kazlauskas A. VEGF-A engages at least three tyrosine kinases to activate PI3K/Akt. Cell Cycle 2012;11:2047-8. [Crossref] [PubMed]
17. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857-68. [Crossref] [PubMed]
18. Camaré C, Pucelle M, Nègre-Salvayre A, et al. Angiogenesis in the atherosclerotic plaque. Redox Biol 2017;12:18-34. [Crossref] [PubMed]
19. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 2008;8:579-91. [Crossref] [PubMed]
20. Dakowicz D, Zajkowska M, Mroczko B. Relationship between VEGF Family Members, Their Receptors and Cell Death in the Neoplastic Transformation of Colorectal Cancer. Int J Mol Sci 2022;23:3375. [Crossref] [PubMed]
21. Katayama Y, Uchino J, Chihara Y, et al. Tumor Neovascularization and Developments in Therapeutics. Cancers (Basel) 2019;11:316. [Crossref] [PubMed]
22. Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol 2009;6:465-77. [Crossref] [PubMed]
23. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427-34. [Crossref] [PubMed]
24. Lopes-Coelho F, Martins F, Pereira SA, et al. Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 2021;22:3765. [Crossref] [PubMed]
25. Kazazi-Hyseni F, Beijnen JH, Schellens JH. Bevacizumab. Oncologist 2010;15:819-25. [Crossref] [PubMed]
26. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. [Crossref] [PubMed]
27. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013;14:29-37. [Crossref] [PubMed]
28. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:60-5. [Crossref] [PubMed]
29. Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study. J Clin Oncol 2023;41:3663-9. [Crossref] [PubMed]
30. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25:1539-44. [Crossref] [PubMed]
31. Prager GW, Taieb J, Fakih M, et al. Trifluridine-Tipiracil and Bevacizumab in Refractory Metastatic Colorectal Cancer. N Engl J Med 2023;388:1657-67. [Crossref] [PubMed]
32. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016;27:1386-422. [Crossref] [PubMed]
33. Yoshino T, Arnold D, Taniguchi H, et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 2018;29:44-70. [Crossref] [PubMed]
34. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103-11. [Crossref] [PubMed]
35. Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28:2144-50. [Crossref] [PubMed]
36. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008;26:5422-8. [Crossref] [PubMed]
37. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. [Crossref] [PubMed]
38. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227-34. [Crossref] [PubMed]
39. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013;31:3004-11. [Crossref] [PubMed]
40. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 2013;31:4349-57. [Crossref] [PubMed]
41. Garcia J, Hurwitz HI, Sandler AB, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020;86:102017. [Crossref] [PubMed]
42. Park S, Kim TM, Han JY, et al. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol 2024;42:1241-51. [Crossref] [PubMed]
43. Shiraishi Y, Kishimoto J, Sugawara S, et al. Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol 2024;10:315-24. [Crossref] [PubMed]
44. Watanabe S, Furuya N, Nakamura A, et al. A phase II study of atezolizumab with bevacizumab, carboplatin, and paclitaxel for patients with EGFR-mutated NSCLC after TKI treatment failure (NEJ043 study). Eur J Cancer 2024;197:113469. [Crossref] [PubMed]
45. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473-83. [Crossref] [PubMed]
46. Tewari KS, Burger RA, Enserro D, et al. Final Overall Survival of a Randomized Trial of Bevacizumab for Primary Treatment of Ovarian Cancer. J Clin Oncol 2019;37:2317-28. [Crossref] [PubMed]
47. Oza AM, Cook AD, Pfisterer J, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015;16:928-36. [Crossref] [PubMed]
48. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-45. [Crossref] [PubMed]
49. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2017;18:779-91. [Crossref] [PubMed]
50. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302-8. [Crossref] [PubMed]
51. Lorusso D, Mouret-Reynier MA, Harter P, et al. Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Int J Gynecol Cancer 2024;34:550-8. [Crossref] [PubMed]
52. Freyer G, Floquet A, Tredan O, et al. Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group. Nat Commun 2024;15:1985. [Crossref] [PubMed]
53. Drew Y, Kim JW, Penson RT, et al. Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study. Clin Cancer Res 2024;30:50-62. [Crossref] [PubMed]
54. Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 2014;370:734-43. [Crossref] [PubMed]
55. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet 2017;390:1654-63. [Crossref] [PubMed]
56. Tewari KS, Colombo N, Monk BJ, et al. Pembrolizumab or Placebo Plus Chemotherapy With or Without Bevacizumab for Persistent, Recurrent, or Metastatic Cervical Cancer: Subgroup Analyses From the KEYNOTE-826 Randomized Clinical Trial. JAMA Oncol 2024;10:185-92. [Crossref] [PubMed]
57. Oaknin A, Gladieff L, Martínez-García J, et al. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet 2024;403:31-43. [Crossref] [PubMed]
58. Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26:2992-8. [Crossref] [PubMed]
59. Boige V, Malka D, Bourredjem A, et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist 2012;17:1063-72. [Crossref] [PubMed]
60. Lee MS, Ryoo BY, Hsu CH, et al. Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study. Lancet Oncol 2020;21:808-20. [Crossref] [PubMed]
61. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-905. [Crossref] [PubMed]
62. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40. [Crossref] [PubMed]
63. Wick W, Gorlia T, Bendszus M, et al. Lomustine and Bevacizumab in Progressive Glioblastoma. N Engl J Med 2017;377:1954-63. [Crossref] [PubMed]
64. Johnson DR, Leeper HE, Uhm JH. Glioblastoma survival in the United States improved after Food and Drug Administration approval of bevacizumab: a population-based analysis. Cancer 2013;119:3489-95. [Crossref] [PubMed]
65. Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014;370:709-22. [Crossref] [PubMed]
66. Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370:699-708. [Crossref] [PubMed]