The role of bevacizumab on tumour angiogenesis and in the management of gynaecological cancers: A review

Biomedicine & Pharmacotherapy 102 (2018) 1127–1144

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The role of bevacizumab on tumour angiogenesis and in the management of gynaecological cancers: A review

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Dinesh Kumar Chellappana, , Kun Hooi Lengb, Lee Jia Jiab, Nur Amirah Binti Abdul Azizb, Wong Chun Hoongb, Yap Cheng Qianb, Fam Yi Lingb, Gwee Sing Weib, Tiong Yingb, ⁎ Jestin Chelliana, Gaurav Guptac, , Kamal Duad a

Department of Life Sciences, School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia c School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, 302017, Jaipur, India d Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Sydney, NSW 2007, Australia b

A R T I C LE I N FO

A B S T R A C T

Keywords: Bevacizumab Cervical cancer Endometrial cancer Ovarian cancer

Objective: The study aims to analyze the effectiveness of bevacizumab in addressing the complications associated with gynecological cancers and evaluates effective treatments for various gynecological cancers. Methods: The study follows a systematic review approach that has been implemented to analyze the qualitative published data from previous studies. Studies related with the trials of angiogenesis and bevacizumab were selected in the review. Results: In general, the management of gynecological cancers include chemotherapy, surgery and radiation therapy. Results suggest bevacizumab as an effective treatment modality for cervical and several other cancers. Overall, bevacizumab showed promising results in improving the overall survival rate of gynecological cancer patients through the combination of bevacizumab with other chemotherapeutic agents. Conclusion: Bevacizumab possess less documented adverse effects when compared to other chemotherapeutic agents. The manifestation and severity of adverse effects reported varied according to the chemotherapeutic agent(s) that were used with bevacizumab in combination therapy. Overall, bevacizumab effectively improved the survival rate in patients with several gynaecological cancers.

1. Introduction Gynecological cancers are a group of cancers involving the female reproductive system, that includes cancers of the ovary, cervix, endometrium, fallopian tube, vagina and vulva [1]. This review focuses on the three most common types of gynecological cancers, which are cervical, endometrial and ovarian cancer. The current treatment for gynecological cancers include surgery for dissectible tumors; chemotherapy and radiotherapy for in-dissectible tumors [2–9]. However, even with the combination of both chemotherapy and radiotherapy, the prognosis of gynecological cancers remains poor [10] due to tumor angiogenesis [11]. Angiogenesis is defined as the formation of new blood capillaries [11,12], which is a complex process that promotes vascular endothelial growth factor (VEGF) and other proangiogenic factor expression, thus enhancing metastasis [11,12]. Almost 50% of the human cancers known were found to have the expression of the VEGF family and VEGF receptors

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[13]. These factors are known to worsen the prognosis of cancers of the uterine cervix [14], endometrium [15], and ovary [16–18]. Hence, the novel therapeutics in recent years suggested that Bevacizumab (Avastin®, Genentech), a humanized monoclonal antibody that acts as a direct VEGF inhibitor [12], approved by FDA in 2014 may show some clinical benefit in improving the overall survival rate of gynecological cancer patients [19–21]. Cervical cancer is now ranked the fourth most common female cancer, with an estimated 527,600 new cases diagnosed and resulting in 265,700 mortality worldwide every year [22]. In the United States of America (USA), the estimated number for new cervical cancer cases in 2015 was 12,900 with 4100 estimated number of deaths [23]; among which the squamous cell carcinoma being the major type of cancer [24]. The main etiology of cervical cancer is the chronic infection by Human Papillomavirus (HPV), with the HPV Subtypes 16 and 18 accounted for 70% of all cervical cancer cases worldwide [24]. The incidence of cervical cancer is higher in developing countries with an

Corresponding authors. E-mail addresses: [email protected] (D.K. Chellappan), [email protected] (G. Gupta).

https://doi.org/10.1016/j.biopha.2018.03.061 Received 11 February 2018; Received in revised form 9 March 2018; Accepted 11 March 2018 0753-3322/ © 2018 Elsevier Masson SAS. All rights reserved.

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3. Material and methods

estimated 2.716 million population of ages from 15 to 44 years, who are in the high risk group [24]. Africa, Central and South America are the countries with the highest incidence rates of cervical cancer; whereas developed countries such as North America, Australia, New Zealand and parts of Western Europe have the lowest incidence rates [22]. Overall, 90% of deaths caused by cervical cancer happens in the developing countries [22,24], where India is accounted for one-fourth of the total cervical cancer deaths [22]. Endometrial cancer with an estimated 319,600 new cases globally in 2012 alone [22], is ranked as the sixth most common type of cancer in women [22,25]. Endometrial cancer, which occurs in the lining of the uterus, is the most common type of cancer occurring in the uterus [26]. Unlike cervical cancer, the incidence of endometrial cancer is found higher in high-income and developed countries with the higher risk group being post-menopausal women [25]. North America, Central and Eastern Europe have the highest incidence. On the contrary, countries with middle or low-income such as Western Africa have the lowest incidence [25]. Cancers of the uterine body and endometrium have an estimated total of 54,870 newly diagnosed cases, with an estimated 10,170 fatalities for endometrial cancer in the USA alone in 2015 [10]. Majority of the endometrial cancer cases are of adenocarcinoma origin [26]. For local stage or stage I endometrial cancer that represents 67% of all endometrial cancer cases diagnosed [27,28], the 5-year survival rate is significantly high at 95.3% [28,29] due to presentation of early symptoms [25]. Other stages of endometrial cancers are relatively rare, but associated with worse prognosis [27]. In general, an average of 69% [27] of the diagnosed endometrial cancer patients will survive for 5 years upon detection [25]; hence, endometrial cancer only contributes less than 2% of cancer death cases in women [25,27]. Ovarian cancer has an estimated 238,700 new cases each year with 151,900 estimated deaths in 2012, ranking it as the seventh most common cancer in females [26,27]. In the USA, the incidence of ovarian cancer was estimated to be around 21,290 with about 14,810 deaths in 2015 alone [27]. Almost all the cases diagnosed are of epithelial carcinoma origin [26]. Similar to endometrial cancer, the incidence rate of ovarian cancer is higher in developed countries and the risks increase with age, although, less cases occur in post-menopausal women [26]. In 2012, the incidence rate is more than 9 per 100,000 women in developed countries in Central and Eastern Europe [29]; and on the contrary, the incidence rate is 5 per 100,000 [29] women in developing countries such as parts of Africa [29,30]. The mortality rate was 5 and 3.1 per 100,000 in developed and developing countries respectively [28]. Ovarian cancer is known as a ‘silent killer’ in females due to absence of symptoms in early stages. Hence, ovarian cancer is usually fatal, with an average of 60% of the diagnosed cases succumbing to death within 5 years upon detection [29–31]. Although the incidence and survival rates between endometrial cancer and ovarian cancer are different, the risks for both cancers are similar. The main reason of higher incidence of both of these cancers in developed countries is due to the use of estrogen-only hormone replacement therapy [32–35]. Other significant factors that increase the risk include sedentary lifestyle, obesity, not bearing children, having early menarche and late menopause [35–40]. Angiogenesis has been the main characteristic feature of these cancers. Antiangiogenic agents such as bevacizumab have been promising in prolonging the survival rate in these patients. The aim of this study is to review the antiangiogenic properties of bevacizumab in the treatment of gynecological cancers.

The review was carried out from early 2015 until August 2016. Literature dating until August 2016 were included in the review. Most of the search was performed on the online search engines namely Google, Google Scholar and Medline followed by various other electronic online bibliographic databases. Additional links to electronic research databases were separately searched. For PubMed search, controlled vocabularies such as MeSH (Medical Subject Headings) were used. ERIC Thesaurus terms and a combination of related keywords were also used. The source of data selection was done from reputed international journals. 3.1. Study selection All relevant studies ranging from clinical trials, pre-clinical studies and laboratory findings were included in the review. Studies concerning other cancers and non-relevant topics were omitted. All included studies and documents were assessed for the quality of the work done. A team of six reviewers among the authors were involved in the assessment of the documents, which included homogeneity, relevance, quality, and language. The recent research studies, which were having a positive correlation of angiogenesis with the effect of bevacizumab, were selected as a source of information to this topic. The effectiveness in treatment of various gynecological cancers was analyzed with a thorough review of the relevant studies. The effectiveness of several other drugs was also examined to compare and correlate the effects and side effects of bevacizumab. There were some studies that have proven the side effects of bevacizumab; however, most of them were favoring the concept. 4. Results and discussion 4.1. Clinical problem 4.1.1. Angiogenesis Angiogenesis is a process of growing, sprouting or developing new blood vessels from the pre-existing vasculature or intussusception. In other words, angiogenesis is the separation of an existing blood vessel into two and more new blood vessels from the parent blood vessel [41–43]. Angiogenesis is tightly regulated by the balance of proangiogenic and antiangiogenic factors [44]. Generally, angiogenesis undergoes four stages as shown in Fig. 1 [41,45,46]. 4.1.2. Types of angiogenesis Angiogenesis can be classified into two types, which are sprouting and non-sprouting angiogenesis [47]. The latter is also referred to as intussusception [47]. Sprouting angiogenesis is the growth of new blood vessels from the pre-existing blood vessels and usually occurs during the development of yolk sac and embryo [47,48]. On the other hand, non-sprouting angiogenesis is the enhancement of the complexity of the newly formed blood vessels into a vascular network [49]. The development of non-sprouting angiogenesis can take minutes to hours as it does not require endothelial cells to proliferate [49]. Both sprouting and non-sprouting angiogenesis are observed in the development of organs or tissues vascularization such as yolk sac, heart and lungs [47]. Therefore, both types of angiogenesis are equally important in aiding tumor growth because a highly vascularized tumor will ensure tumor survival, growth and allow metastasis to other parts of the body. However, the development into either sprouting or non-sprouting angiogenesis is dependent on the number of existing blood vessels in that specific organ or tumor [50,51].

2. Statement of objectives The study aims to analyze the effectiveness of antiangiogenic agents such as bevacizumab to address the complications associated with gynecological cancers and evaluate effective treatments for various gynecological cancers.

4.1.3. Occurrence of angiogenesis Angiogenesis is a common process that occurs during many physiological conditions such as in the development of placenta and fetus 1128

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Fig. 1. General stages of angiogenesis. Adapted from Shinkaruk et al., Nishida et al., and Cook et al., (41,45,46). Note: The figure shows the key stages in the process of angiogenesis. The figure summarizes the steps involved in the formation of new capillary blood vessels. The steps include protease production, endothelial cell migration and proliferation, vascular tube formation, anastomosis of newly formed tubes, synthesis of a new basement membrane and incorporation of pericytes. Localized degradation on the parent vessel of the basal membrane and the surrounding extracellular matrix due to activation of endothelial cells. The activation of the endothelial cells is triggered by various factors such as hypoxia, growth factors, cytokines, endogenous modulators or trace elements and injury. The degraded endothelial cells undergo orientated migration into the surrounding extracellular matrix. The migrated endothelial cells undergo proliferation. The proliferated endothelial cells undergo differentiation and rearrange themselves into tubular structures to form a new basal lamina, which subsequently form a new vascular network that supports the growth of the tissues. Abbreviations: EC, endothelial cells; BM, basement membrane; P, pericytes; gal-1, galectin-1; gal-3, galectin-3; gal-8, galectin-8; gal-9#5, splice variant galectin-9 lacking exon 5.

tissues will not divide and undergo angiogenesis except in conditions such as reproductive cycle, tissue repair of wound or ulcers and tissue growth [50] [56]. This is because there is a balance between local proangiogenic and antiangiogenic factors in physiological conditions

[47,51–53], during endochondral bone formation which is essential for the development of longitudinal bone [54] and the proliferation and decidualization in the endometrium during the menstrual cycle [53,55]. Under normal circumstances, endothelial cells in normal adult 1129

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Fig. 2. Proangiogenic and antiangiogenic factors involved in angiogenesis, adapted from Nagy et al, Kerbel and Reinmuth et al (85, 86). Abbreviations: VEGF, vascular endothelial growth factor; aFGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; PIGF, placental growth factor; PDGF, platelet derived growth factor.

vascular network is also crucial for the metastatic spread of tumor [6]. It has been hypothesized by Folkman in 1971 that the survival and growth of tumor depends upon the development of new blood vessels [62,63]. It is been thought that angiogenesis is triggered as soon as the tumor reaches a diameter of 0.4mm [15]. Without the presence of vascular support, tumors cannot continue to grow and remain in situ for several months to years which eventually leads to apoptosis [64,65].

[50]. Thus, endothelial cells have low mitotic activity and are considered to be one of the extremely stable cell when compared to other rapidly growing cells such as the cells of hair follicles and skin [56]. However, if this balance between proangiogenic and antiangiogenic factors gets disrupted, whereby proangiogenic factors predominate, angiogenesis is considered abnormal and it is known to be a “common denominator” [50] in many pathological conditions such as tumors, diabetic proliferative retinopathy, psoriasis, atherosclerosis and rheumatoid arthritis [57–60].

4.1.5. Angiogenesis in tumor growth As mentioned earlier, tumors are often deprived of oxygen and essential nutrients due to their greater distance from the closest blood vessels, therefore it leads to hypoxia in tumors. It is shown that hypoxia plays a key role in stimulating angiogenesis [39]. In the state of hypoxia, tumors produce hypoxia inducible factors (HIFs), which are HIF-α and HIF-β [65]. Under the circumstances when there is low oxygen concentration, HIF-α is synthesized and then bound to HIF-β to form heterodimer [65–69]. The heterodimer activates a transcription process in the nucleus to produce several cytokines and growth factors such as vascular endothelial growth factor (VEGF),

4.1.4. The importance of angiogenesis in tumor growth (13) In the absence of angiogenesis, cancer cells or tumor can only grow up to 1–2 mm in diameter [47,61]. As tumor grows larger, the expanding tumor constantly lacks oxygen and essential nutrients such as glucose and amino acids due to their greater distance from the closest blood vessels, whereby, only passive diffusion of the oxygen and nutrients can occur [13,61]. Consequently, the tumors begin to develop hypoxia [34]. Therefore, in order to grow beyond 2mm in diameter, angiogenesis must occur [13,34]. Furthermore, the growth of the 1130

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platelet derived growth factor (PDGF), transforming growth factor-α, interleukin-1 and interleukin-8 [65–69]. However, HIFs are inactive in the presence of oxygen [67]. In a detailed mechanism, hypoxia induces VEGF production by enhancing the rate of transcription for VEGF and the stability of VEGF messenger ribonucleic acid (mRNA) in the nucleus [67,70,71]. This may result in an increased amounts of the synthesized proangiogenic factors such as VEGF [72]. The VEGF secreted, generates a chemotactic gradient to activate and enroll endothelial cells away from the pre-existing vascular network [65,69]. The activated endothelial cells generate matrix metalloproteinases (MMPs) [66,68], which degrade extracellular matrix, allowing the endothelial cells to migrate towards the tumor and beginning to divide [66,73–75]. Once a vascular network is formed, it can support the continued growth of tumor by transporting oxygen and essential nutrients more efficiently to the tumor and remove waste products away from the tumor [65]. It is often seen that the tumor blood vessels display various functional and structural malformation such as unusual leakiness and tortuous network [76–79], uneven distribution, irregular branching patterns and loss of vascular integrity causing disturbed blood flow [80]. On the other hand, normal vessels have even distribution, hierarchy and are coated with smooth muscle cells [81]. The former properties can be considered as the hallmarks of a tumor due to the proliferation of endothelial cells resulting in an increased in the number of tumor cells [69,82,83]. Because tumor blood vessels have structural malformation, macromolecules such as plasma proteins and fibrinogens are able to penetrate into the tumor. Fibrinogens will then undergo polymerization to produce fibrin gel clots [69]. This process encourages tumor to expand due to entrapment and protection of the growth factors from degradation provided by the fibrin gel clots [84].

VEGF family namely VEGF-A, B, C, D, E and placenta growth factor (PlGF) [93]. Among members of the VEGF family, VEGF-A, B, C and E are involved in angiogenesis while VEGF-C and D are involved in lymph vessel proliferation [93–95]. VEGF-A is the most widely studied member and has important functions in mediating cancer cell survival, proliferation and migration [95]. Besides that, VEGF-A is a potent mitogen and has the capability to enhance the vascular endothelial cells growth [15,24,38,89]. There are 4 isoforms of VEGF-A (VEGF-A121, VEGF-A165, VEGF-A189 and VEGFA206) [96]. Among the four isoforms, VEGF-A165 constitutes the major form [96]. The overexpression of VEGF-A165 occurs in many types of human tumors [97] and it is triggered by various factors such as tumor hypoxia, activation and/ or expression of certain oncogenes (fos, vhl, ras, and src), downregulation of p53, hormones such as androgens and estrogens and the proangiogenic factors that are listed in Fig. 2 [98–102]. When a VEGF is produced from cells such as epithelial cells of the retina, macrophages, and cancer cells, it binds to VEGF receptor (VEGFR), which is a tyrosine kinase receptor present on the outer surface of endothelial cells to trigger a cascade of events resulting in angiogenesis [103–105]. There are three types of VEGFRs, namely VEGFR-1 or fms-like-tyrosine-kinase (Flt-1) [106,107], VEGFR-2, also known as kinase domain region or fetal liver kinase-1 (KDR or Flk-1) [108–110] and VEGFR-3 [111,112]. These receptors are located on bone marrow-derived cells and vascular endothelial cells [25]. It is believed that VEGFR-2 conveys the majority of proangiogenic signaling of VEGF-A and therefore these two play key roles in cancer angiogenesis ([113–115]; [116]). The VEGF signaling pathway and various signaling molecules involved in the pathway are shown in Fig. 3.

4.2. Factors involved in angiogenesis

4.3. Antiangiogenic agents

Angiogenesis is controlled by both the activating (proangiogenic) and inhibiting (antiangiogenic) factors [84]. Many proteins have been discovered as proangiogenic and antiangiogenic factors which are listed in Fig. 2. The level of angiogenic factors expression indicates the aggressiveness of the tumor cells [85,86]. The aggressiveness of tumor cells is greater when the level angiogenic factors expression is high. Upregulation of proangiogenic factors itself is insufficient to initiate angiogenesis; however, with the concurrent downregulation of antiangiogenic factors, it is shown to induce angiogenesis [87]. Hence, it is been thought that the tumor angiogenic switch has to be stimulated to produce an imbalance in the ratio of proangiogenic to antiangiogenic factors [88]. Angiogenic switch is the ability of a tumor to trigger the tumor vasculature development [86] and transform the tumor from latent phase into a metastatic and invasive phase [89]. Angiogenic switch can take place at various stages in the tumor progression pathway, depending on the environment and the type of tumor presented [86]. When the condition is more favorable to proangiogenic factors, the ratio of proangiogenic to antiangiogenic factors is high, angiogenesis is activated [88]. On the contrary, if the ratio is low, angiogenesis is inhibited [89]. Therefore, in order for the tumor to grow beyond 2mm, the ratio of the proangiogenic to antiangiogenic factors has to be high to initiate angiogenesis [88]. A detailed description for every proangiogenic and antiangiogenic factors is beyond the scope of this review [90,91], but vascular endothelial growth factor (VEGF) will be highlighted in this review as this has gained more attention [91] in recent decades and is one of the most potent proangiogenic factors identified to trigger angiogenesis [92].

Since angiogenesis plays a key role in the development of tumor and there are limited processes in normal adults, developing antiangiogenic agents is definitely an attractive anticancer target [117]. It is well known that cancer cells produce VEGF, particularly the VEGF-A that targets on the VEGFR-2 to promote the survival, migration and invasion of tumor, and therefore, it is the main target of antiangiogenic agents in cancer therapy [56,63,118]. Inhibition of VEGF function can lead to the inhibition of the new blood vessels formation surrounding a tumor, and consequently arrest the tumor growth by depriving essential nutrients and oxygen [119]. This targeted approach has become one of the most significant approaches in cancer therapy in recent years [118]. Interestingly, many conventional chemotherapeutic agents such as cytotoxic agents and the hormonal ablation therapy possess unexplored antiangiogenic activity [84]. Various antiangiogenic agents and compounds known currently are either already available in the market or still undergoing clinical trials [80]. The list of common antiangiogenic agents used in the management of cancer treatments are listed in Table 1. Apart from the compounds listed above, plant-derived compounds have gained remarkable attention for their possible therapeutic outcomes in cancer therapy [120–122]. Many plant-based medicinal compounds or phytochemicals have lately been assessed for its antiangiogenic properties in the cancer treatment [123–125]. Examples of phytochemicals that possess antiangiogenic activities are Curcuma longa (turmeric), Panax ginseng (ginseng), Zingiber officinalis (ginger), Camellia sinensis (green tea) and Withania somnifera (Withaferin A) [126]. Although, plant-based medicinal compounds have shown promising antiangiogenic effects, the potential drawbacks such as poor bioavailability when consumed in its natural form; hence its effectiveness, it is still questionable as compared to the antiangiogenic agents available in the market [126]. Therefore, more investigations are required to be done to understand the effectiveness of plant-derived compound in anticancer therapy [127,128].

4.2.1. Vascular endothelial growth factor (VEGF) VEGF is a family of proteins that regulates angiogenesis [92]. In the last few decades, scientists have discovered numerous members of 1131

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Fig. 3. Signaling pathways initiated by VEGF that leads to angiogenesis modified from Cook et al (25). Note: Vascular endothelial growth factor (VEGF), one of the proangiogenic factors, binds to the vascular endothelial growth factor receptor (VEGFR), a tyrosine kinase receptor, causing the receptor to undergo dimerization and auto-phosphorylation of the receptor complex. Consequently, the phosphorylated receptor interacts with different cytoplasmic signaling molecules, leading to signal transduction and finally angiogenesis. Abbreviations: MEK, mitogen-activated protein kinase; ERK, extracellular-regulated kinase; PIP2, phosphatidylinositol 4, 5-bisphosphate; PIP3, phosphatidylinositol (3, 4, 5)-trisphosphate; PI3K, phosphoinositide 3-kinase; PDK-1, phosphoinositide dependent kinase-1; ILK, integrin-linked kinase; PKB, protein kinase B.

Table 1 List of common antiangiogenic agents identified; adapted from Cook et al and Ferrara et al (80). Roles

Antiangiogenic agents

VEGF inhibitors MetAP-2 inhibitors TNF-α inhibitors RTK inhibitors Monoclonal Antibodies Directed at EGFR PI3K/AKT pathway inhibitors mTOR inhibitors Farnesyltransferase inhibitors

Bevacizumab (Avastin®), Aflibercept (VEGF-Trap, AVE0005) Fumagillin, TNP-470 Thalidomide (Thalomid®); Lenalidomide (Revimid®, CC-5013) and Pomalidomide (Actimid®, CC-4047) (thalidomide deriviatives) Sunitinib (Sutent®, SU11248), Sorafenib (Nexavar®, BAY 43-9006), Erlotinib (Tarceva®, OSI-774), Imatinib (Gleevec® STI571) etc Cetuximab (Erbitux®) and Panitumumab (Vectibix®, ABX-EGF) Perifosine, Wortmannin Rapamycin (sirolimus); Temsirolimus and Everolimus (rapamycin analogues) Tipifarnib (Zarnestra®, R115777)121 and Lonafarnib (Sarasar®, SCH66336)122

Abbreviations: VEGF, vascular endothelial growth factor; MetAP-2, methionine aminopeptidase; TNF-α, tumor necrosis factor-alpha; RTK, receptor tyrosine kinases; EGFR, Endothelial growth factor receptor; P13K, phosphatidylinositol 3-kinase; mTOR, mammalian target of rapamycin. 1132

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as compared when used in combination with other chemotherapeutic agent(s) [38]. However, caution has to be taken when using in combination with other antiangiogenic agents in an effort to enhance antiangiogenic effect [141]. For example, the concomitant use of tyrosine kinase receptor inhibitor, sorafenib with bevazicumab during a Phase I clinical trial in patients diagnosed with solid tumor caused excessive toxicities such as proteinuria, thrombocytopenia and hand-foot syndrome [141,142]. This combination therapy has limitations due to the manifestations of adverse effects [141]. Unfortunately, even though bevacizumab has shown considerable improvements in patients with cancer, development of resistance to bevacizumab can occur as the cancer progresses [26]. The mechanism of resistance in anti-VEGF compounds such as bevacizumab is not well understood, but the two proposed mechanism of resistance are adaptive resistance and intrinsic resistance [143]. The proposed mechanisms of resistance overlaps with each other [143,144]. Adaptive resistance involves the upregulation of alternative proangiogenic factors such as fibroblast growth factors and placental growth factors, and vascular progenitor cells enrolment [144,145]. On the other hand, intrinsic resistance involves excessive signals of proangiogenic factors and vascular protection of existing inflammatory cells [26]. It has been shown that antiangiogenic therapy is more effective in established metastatic tumors or localized tumors in pre-clinical and clinical studies, but the results remained inconclusive for the case of early stage of tumor metastasis [146]. Apart from its resistance, antiVEGF agents such as bevacizumab are more expensive than other chemotherapy medications [135]. The high cost of bevacizumab may also deter patients from accessing this medication (119). Although, bevacizumab was approved by the US FDA in 2014 for various indications, but medical advisory boards of several countries such as England and Wales suggested that the cost-effectiveness of the combination of bevacizumab and other chemotherapy medications is unlikely to be lowered [147]. Hence, it is important to understand more regarding the mechanism of action as well as its modes of resistance of bevacizumab for its effective use in the future [137].

4.4. Bevacizumab as antiangiogenic agent Bevacizumab is a recombinant, humanized monoclonal antibody derived from murine VEGF monoclonal antibody which is made up of approximately 93% of human and 7% of murine protein sequence [129,130]. Bevacizumab is also a monoclonal mice antibody A4.6.1 developed from a mouse by immunizing with human VEGF-165 [130]. Bevacizumab binds selectively to VEGF-A and does not bind to the other VEGF family members, thus inhibiting VEGF-A from binding to the tyrosine kinase receptor (VEGFR) that can initiate signaling cascade for angiogenesis in tumor [67,100]. There are a few postulated mechanism of actions of bevacizumab in inhibition of the VEGF signaling in angiogenesis, including blocking of new blood vessels growth, exhibiting direct effects on tumor such as suppression of anti-apoptotic autocrine signals and modifying the function of vascular and blood flow of tumor by enhancing delivery and increasing effectiveness of chemotherapeutic agents [131–135]. In 2004, the Food and Drug Administration (FDA) had approved bevacizumab to be used in combination with 5-fluorouracil [136] for the treatment of breast cancer, non-small cell lung cancer, colorectal carcinoma, platinum-resistant ovarian cancer [137] and glioblastoma [34]. Bevacizumab has been found to be more effective on tumors when it is used in combination than when is used as a single agent [131]. Bevacizumab has similar pharmacological and biochemical properties to the parent antibody with lower immunogenicity and longer half-life of 17–21 days [41]. However, adverse effects associated to bevacizumab such as hypertension, thromboembolic events, proteinuria, congestive heart failure, hemorrhage, gastrointestinal perforation, and hemoptysis have been observed in patients [137,138]. The most common adverse effect associated with bevacizumab is hypertension [138]. It has been found that VEGF is associated in modulating healthy vascular endothelium [139]. However, when a VEGF inhibitor such as bevacizumab is used, it will decrease the production of nitric oxide, which is essential for regulation of blood pressure, thus increasing the risk of hypertension [139]. It is also shown that long term used of bevacizumab can results in reversible proteinuria [140] (Fig. 4).

4.6. Use of bevacizumab in gynecological cancers 4.5. Clinical effectiveness of bevacizumab in targeting VEGF 4.6.1. Cervical cancer In the USA, more than ten thousand cases of cervical cancer are diagnosed each year; and to that, nearly half of this number of lives have been claimed by this type of cancer [148]. However, cervical cancer incidence has a large geographical variation due to the difference in availability of screening for early detection and the prevalence of human papillomavirus (HPV) infection [149–151]. Over the past 40 years, the implementation of screening programs have reduced cancer rates by 65% [151]. However, cervical cancer incidence among young women in Europe, Central Asia, Japan, and China is on the rise due to HPV infection from changing sexual behaviors [152]. On the contrary, the Middle East have the lowest incidence of cervical cancer due to societal disapproval of extramarital sexual activity [153]. Cervical cancer starts with its pre-invasive state which is the presentation of abnormal vascularity during colposcopic evaluation. After the chronic infection with human papillomavirus (HPV) as well as the integration of viral DNA such as oncoproteins E6 and E7 into the host cells, malignancy begins through the inactivation of tumor suppressor genes such as p53 and pRb [154]. Finally, these events lead to an accumulation of hypoxia inducible factor 1 (HIF-1) protein, a strong stimulus to increase expression of VEGF during tumor hypoxia [155]. Besides that, emerging data also suggests that HPV may directly stimulate the VEGF production [156,157]. Hence, VEGF inhibition appears to be a definite therapeutic strategy in the treatment of cervical cancer [158]. There are a number of studies which have been successfully reported on the significance of VEGF expression during cervical carcinogenesis [158–161]. An analysis of 117 women with stage

Monotherapy with bevacizumab may not be sufficient to inhibit VEGF and angiogenesis, as the tumor develops resistance as frequently

Fig. 4. Structure of bevacizumab, reproduced from Ranieri et al (142). Notes: The black dots indicate murine grafted on the disulfide backbone linked with heavy and light chains consisting variable (VH and VL) and constant regions (CH and CL). 1133

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(RTOG) 0417 study, 49 women with bulky Stage IB-IIIB tumors were given bevacizumab of 10mg/kg every 2 weeks for 3 cycles in combination with definitive radiotherapy and concurrent cisplatin [168]. This study was carried out to evaluate the safety and efficacy of the above treatment with a median follow-up of 12.4 months. The results of the study showed that only 2 out of 46 patients developed gastrointestinal (GI) adverse events but no life-threatening event or death was observed. The GI toxicity was relatively mild. Although we emphasize our initial concern on the synergistic effects between radiation and bevacizumab treatment, RTOG 0417 study proved that there is no GI perforations or fistulas seen after the combination therapy [168]. Based on the results from these studies, it is shown that there is a major difference in the occurrence and severity of the side effects related to different bevacizumab combination therapies. However, it is also shown that the results on the effectiveness of bevacizumab in treatment of cervical cancer are consistent. A study showed that the benefits of bevacizumab use in metastatic cervical cancer is uncertain in approximately 17% of patients [167]. Despite that, the role and activity of bevacizumab in earlier disease stages should be carefully evaluated [167]. Based on the data obtained in one of the studies, it was shown that bevacizumab is more beneficial for patients with squamous cell carcinoma in comparison with patients with adenocarcinoma [167].

Ib cervical cancer showed that high VEGF expression is associated with deep tumor invasion, pelvic failure and pelvic node metastases [162]. Due to the nature of cervical cancer oncogenesis via increased expression of VEGF, it is postulated that cervical cancer tumor is particularly susceptible to bevacizumab [13]. In a Phase II clinical trial conducted by the Gynecology Oncology Group (GOG) (protocol 227C), 46 recurrent cervical cancer patients were treated with a single bevacizumab dose of 15mg/kg for every 3 weeks [162]. This trial yielded a 35% response rate. A median overall survival (OS) of 7.3 months (95% CI, 6.1–10.4 months) and a median progression free survival (PFS) of 3.4 months (95% CI, 2.5-4.5 months) were obtained [162]. The results suggested that bevacizumab alone is effective in suppressing recurrent cervical cancer. In 2009, a four-arm Phase III clinical trial, GOG 240 was conducted to explore the effectiveness of antiangiogenic therapy in patients with recurrent, persistent or metastatic cervical cancer [163]. In this trial, 452 patients were given bevacizumab in combination with cisplatin and paclitaxel or paclitaxel and topotecan [163]. The bevacizumab-containing arms demonstrated a statistically significant improvement in OS of 17 versus 13.3 months (P = 0.004), PFS of 8.2 versus 5.9 months (P = 0.0002) and a response rate of 48% versus 36% (P = 0.0008) when compared with the non-bevacizumab-containing arms [163]. This significant improvement of the OS in GOG 240 became the first breakthrough for an antiangiogenic agent in gynecologic cancer [88] and led to a change in the standard of care for the treatment of patients with recurrent, persistent or metastatic cervical cancer. Consistent with positive results, both of the clinical trials suggested that bevacizumab is indeed effective in the managemant of recurrent, persistent or metastatic cervical cancer.

4.7. Other considerations of using bevacizumab in cervical cancer 4.7.1. Quality of life The quality of life of patients was evaluated by using the Functional Assessment of Cancer Therapy-Cervix Trial Outcome Index (FACT-Cx TOI) [163]. In this study, the fitted mixed-model estimates for the FACT-Cx-TOI showed there is no significant effect on health-related quality of life with the addition of bevacizumab [163]. The difference is 1.2 points when compared with the patients who did not receive antiangiogenic therapy [163]. In another study, Penson et al., reported the same outcome with the addition of bevacizumab to chemotherapy regimens by assessing 390 evaluable patients [169]. These comparisons concluded that the quality of life of patients undergoing treatment with bevacizumab has no significant difference when compared to treatment with chemotherapy [163].

4.6.2. Side effects of bevacizumab in the treatment of cervical cancer In 2013, a study involving 27 patients with persistent or recurrent cervical cancer who received treatment consisting cisplatin on day 1, topotecan on day 1–3 and bevacizumab on day 1 in a median of 3 treatment cycle was carried out [164]. Toxicity of the treatment was evaluated for all patients. The results showed that most subjects experienced frequent severe hematologic toxicity. 22 patients reported hematology disorders including thrombocytopenia, leukopenia, anemia and neutropenia [164]. The overall response rate was 35%, including 1 complete response and 8 partial responses [164]. The median PFS and OS were 7.1 months and 13.2 months respectively [164]. In another retrospective study, six patients with recurrent cervical cancer were treated with bevacizumab combination therapy (Wright et al., [158]). The combination regimen included intravenous (IV) 5fluorouracil in 5 patients and capecitabine in one patient [158]. Overall, the regimen was well tolerated. The most common toxicity experienced by the patients was anemia; however, there were no complaints of hemorrhagic complications ([165], [158]). The Response Criteria in Solid Tumors (RECIST) was performed to assess the response of the patients [158,166]. Clinical benefit was shown in 67% of the subjects which included 17% each for complete response and partial response as well as 33% with disease stabilization [158]. Besides that, the median time to progression for the four women who demonstrated clinical benefit was 4.3 months [158]. A study of 10 patients with recurrent or metastatic cervical cancer after intensive radiotherapy treatment were given a weekly dose of bevacizumab and gemcitabine/oxaliplatin with or without dasatinib [167]. The effects were studied by Takano et al., and RECIST was again performed to assess the response of the patient [167]. 1 patient experienced a complete remission and 4 other experienced partial remission. The responses were observed in 4 of 5 cases treated with dasatinib and 1 of 5 patients without dasatinib. The overall response rate of this study was 50%. Side effects such as nasal bleeding, neurotoxicity and general fatigue were frequently observed. However, they were all very mild [167]. In another interesting Phase II Radiation Therapy Oncology Group

4.7.2. Cost-effectiveness of bevacizumab A study was carried out to evaluate the cost-effectiveness of bevacizumab in recurrent or persistent and metastatic cervical cancer. In this 5-year model, patients were transitioned through the following states: response, progression, minor complications, severe complications and death [170]. Patients experiencing a health utility per month according to treatment effectiveness were calculated and the results were reported in both quality adjusted cervical cancer life months and years (QALmonth, QALY) [170]. Results of this study showed that the estimated total cost of therapy with bevacizumab is approximately 13.2 times that for chemotherapy alone, resulting in an incremental costeffectiveness ratio (ICER) of $21.083 per month of added life [170]. It is to note that the increased costs for bevacizumab therapy are mainly related to the cost of the drug itself but not the management of bevacizumab-induced complications [170]. It can be assumed that once the cost of bevacizumab is reduced, there will be a decline in the ICER. This suggest the use of less expensive but equally efficacious antiangiogenic agents in cervical cancer treatment as an overall cost reconciliation. It is now clear that antiangiogenic agents such as bevacizumab has a vital role in the management of cervical cancer. Bevacizumab has been successfully studied in many solid tumors [135,171–174] and the use of bevacizumab in advanced cervical cancer and also platinum-resistant ovarian cancer has been approved by the FDA in 2014 [175]. This decision has provided another viable option for the high-risk subgroups to maximize their survival potential. 1134

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the trial, one patient suffered bowel perforation after her first course of therapy; but the rest of the patients were progression-free at 6 months [190]. The reported median PFS was 18 months, with an overall response rate of 73%. The median overall survival was reported to be 58 months [190]. This study concluded that the combination therapy of bevacizumab, paclitaxel, and carboplatin regimen is active and tolerable in advanced and recurrent EMCA. According to a study of 379 patients with recurrent endometrial cancer, only 12% of patients with pelvic recurrences will survive. The chances of survival is even slimmer for patients with distant metastatic endometrial cancer and with combined pelvic and distant failure, with the survival dropped to 5% and only 2% respectively [191]. Thus, there is a strong need for antiangiogenic agents in the setting of recurrent endometrial cancers. Angiogenesis plays an important role in the development and progression of endometrial cancer [192–195]. Abulafia et al., noted a progressive increase in microvessel density (MVD) with the progression from benign endometrium to hyperplasia to invasive cancer [196]. Besides that, the increased vascular density in endometrial cancer tissues is also associated with a poor prognosis. The 5year overall survival was 82% in a cohort of endometrial cancer patients with low microvessel density (MVD), whereas those with high MVD had 30% less chance of survival [197]. In addition, high VEGF expression and MVD are associated with increased tumor vascularization [198,199], lymph vascular space invasion, nodal metastases and advanced stage disease. Therefore, there is a need for VEGF inhibitors such as bevacizumab in the management of endometrial cancer [199]. Fig. 5 shows that bevacizumab reduces the tumor size of endometrial cancers when compared with the control type [195]. The study was performed by using mice model where Athymic mice was injected with Hec50co endometrial cancer cells were treated with vehicle control (saline, n = 8) or bevacizumab (n = 16) for 5 weeks [195]. Even though bevacizumab was unable to arrest tumor growth completely, it contributes to decrease in the size of the tumor. The results from this experiment showed that bevacizumab can reduce the tumor volume by 77% as compared to control treatment [195]. Another study using bevacizumab in 11 patients ranging from 38 to 70 years with multiple-site recurrent endometrial cancer and had received prior chemotherapy was conducted [200]. Among the 11 patients, 9 had epithelial malignancies, including 2 papillary serous carcinomas and 2 mixed epithelial tumors that each contained serous elements, whereas the other 2 patients had uterine leiomyosarcomas [200]. 3 of the patients were in stage I, 1 patient in stage II, 2 patients in stage III and 5 patients in stage IV upon diagnosis [200].Bevacizumab was administered in combination with a chemotherapeutic agent, which is either oral cyclophosphamide, paclitaxel, 5-fluorouracil, capecitabine, doxorubicin, etoposide, carboplatin/docetaxel or gemcitabine/liposomal doxorubicin [200]. The most common side effects reported were anemia, nausea, neutropenia, thrombocytopenia, hypertension and fatigue [200]. Even though there were no case of

Table 2 : Epidemiology of endometrial cancer in the USA in the year 2009, 2010 and 2014, extracted from Jemal et al., and Siegel et al (181–183). Year

Number of newly diagnosed cases

Number of deaths

2009 2010 2014

42160 43000 52630

7780 8000 8590

4.7.3. Endometrial cancer About 53% of incidence of endometrial cancer occurred in more developed countries and it is rated as the fourth and seventh most common gynecologic malignancy of women in the USA and worldwide respectively [176,177]. The epidemiology of endometrial cancer in the USA is shown in Table 2. Almost all endometrial cancer cases are diagnosed in women aged 50 years and above [178]. However, endometrial cancer has a more favorable prognosis than cervical and ovarian cancers with 5-year survival rates around 70% in developing countries [179]. Based on the statistics shown in Table 2, it is indicated that there is a significant increasing trend of the number of deaths and newly diagnosed cases for endometrial cancers from 2009 to 2014. Age is one of the prominent risk factors for the development of endometrial carcinoma, particularly in menopausal women, with the median age being 61 years [180]. According to the US population Surveillance Epidemiology and End Results (SEER) tumor registry data from 2004 to 2008, 19.3% of endometrial cancer incidences were observed in women within 45–54 years old, followed by 32.1% and 40.8% in age group of 55-64 years old and 65-85 years old respectively [181]. In the USA, the overall 5-year survival rate in endometrial carcinoma suffered women is 83%, attributed to early diagnosis of the disease [182]. According to a report by the American Cancer Society, caucasian women have more than 10% higher survival rate than the non-white patients at any corresponding stage [182]. In the past, the most frequently used treatment for endometrial cancer was adjuvant radiotherapy [183]. Adjuvant therapy can be defined as a treatment that is given to the patient as a way to increase the effectiveness of the primary treatment. Other adjuvant therapies include surgery, hormone therapy and chemotherapy [184]. These treatments are used either alone or chronologically depending on the histologic grade and stage of the cancer [184]. There are still concerns regarding these therapies although they are already practiced in clinical settings. For example, adjuvant radiotherapy may not be effective in improving life expectancy of a patient, whereas chemotherapeutic agents are only applicable in the cases of advanced or recurrent endometrial cancers [183]. Besides this adjuvant therapy, another exciting area that can be targeted to be one of the alternative treatments for endometrial cancer is the antiangiogenic therapies. As describribed earlier, angiogenesis is a process of producing new blood vessels and this process plays a vital role for invasion and metastasis in many solid tumor types [185,186]. Hence, antiangiogenic agents now stand as an option in treating endometrial cancer. The most widely used antiangiogenic agent to date is still bevacizumab [187] as it had been approved as a therapeutic choice for several solid tumors in 2010 [188]. This strengthens the fact that bevacizumab is a very potential therapy to manage endometrial cancer. A Phase II clinical trial was conducted in 15 patients to evaluate the effect of adding bevacizumab to paclitaxel and carboplatin as a maintenance therapy on progression-free- survival (PFS) in advanced or recurrent endometrial carcinoma (EMCA) [189]. Patients were initiated with regimen of Paclitaxel (175 mg/m2/3 h), carboplatin (AUC = 5) and bevacizumab (15 mg/kg) using a cycle of 3 weeks, then followed by a maintenance therapy with bevacizumab 15 mg/kg every cycle of 3 weeks for 16 cycles after completion of 6–8 cycles of initial therapy [190]; the median follow-up of the trial being 36 months. Throughout

Fig. 5. Bevacizumab inhibits growth of endometrial cancer in a mouse xenograft model, reproduced from Leslie et al (196). 1135

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conducted in 52 patients for 3 weeks [203]. The tested patients had been previously administered one to two cytotoxic regimens [203]. The results were interpreted by looking at the progression-free survival (PFS), objective RR and toxicity [203]. Early results showed 8 of 53 (15.1%) RR, with 1 complete response and 7 partial responses; 19 of 53 (35.8%) patients were progression free at 6 months, with 2 patients pending at the time of data analysis [203,204]. The median PFS was 4.2 months and the median overall survival (OS) was 10.5 months [203,204]. Based on this result, it was shown that the use of bevacizumab did help in controlling the cancer. However, the overall survival was still poor [204]. Apart from studies conducted to study the effectiveness of bevacizumab as a single agent, there are also studies that combine bevacizumab with other chemotherapy treatments. Indeed, bevacizumab helps to reduce the tumor size of the endometrial cancer but the overall survival is still low. Therefore, there are many studies that suggest, even though the addition of bevacizumab to chemotherapy as a maintenance therapy improved the progression free survival, it was not superior than chemotherapy alone in terms of efficacy [73,144,145,204]. The combination of bevacizumab with chemotherapeutic agents is currently being investigated in a Phase II study conducted by GOG that randomizes patients to receive paclitaxel plus carboplatin plus bevacizumab, or paclitaxel plus carboplatin plus temsirolimus, or ixabepilone plus carboplatin plus bevacizumab as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer [205]. The bevacizumab, paclitaxel, and carboplatin regimen is active and tolerable in advanced and recurrent endometrial cancer. Its impact awaits results of the recently completed randomized Phase II trial [205]. Based on the studies and findings mentioned above, the effectiveness of bevacizumab in treating endometrial cancer has a very bright potential. However, more research in this field is required in the future to establish the efficacy of bevacizumab in the treatment of endometrial cancer. The information on bevacizumab in the treatment of endometrial cancer is still scarce [90].

thromboembolic complications and gastrointestinal tract perforation, there was one case each of grade 4 thrombocytopenia and grade 3 gastrointestinal bleeding reported [200]. Only ten patients were assessable for response. Two partial responses reported were the patients with widespread endometrial cancer and were being treated with combination of bevacizumab and cyclophosphamide [200]. For the two patients with leiomyosarcoma, one patient had stable disease while the other progressed [200]. Among those with epithelial endometrial tumors, 2 patients had partial responses, 2 had stable disease and 4 progressed. The median progression-free interval for the entire cohort was 5.4 months, but the median progression-free interval in the 5 patients who had partial response or stable disease was 8.7 months [200]. In the final follow-up, 6 patients were alive with disease while 5 patients had died from progressive disease [200]. Another study was done to determine the toxicity and survival rates in a trial of concurrent bevacizumab and external beam radiation (EB) for patients with recurrent endometrial or ovarian cancer [201]. 15 women with recurrent endometrial cancer with gross disease involving the vaginal cuff, and/or pelvic nodes and/or para-aortic nodes were enrolled and received bevacizumab during radiation [201]. The adverse effects were assessed at baseline, weekly during treatment and every 3 months for at least 1 year after treatment. All 15 patients had completed the trial and the reported 1-year progression-free survival (PFS) and 3year PFS were 80% and 67% respectively. The overall survival (OS) after 1-year and 3-years were 93% and 80% respectively [201]. Patients that had a vaginal cuff recurrence had similar PFS result and OS of 100% and 75% for 1-year and 3-years OS respectively. Two patients with pelvic node involvement did not recur throughout the entire follow-up period [201]. 5 patients with previous para-aortic node involvement had a 1- and 3-year PFS of 80% and 60% respectively and OS of 80% for both years. Adverse effects reported include thrombosis and 1 embolic event in the setting of metastatic disease; however, no gastrointestinal perforations were reported [201]. The study concluded that treatment of bevacizumab with concurrent radiation provides excellent local tumor control and survival for women with recurrent endometrioid endometrial cancer, particularly those with not dissectible nodes. However, caution must be taken in those at a higher risk of developing metastatic disease given the increased risk of thromboembolic events [201]. This regimen may be considered for recurrent gynecologic malignancies in future trials. Another Phase II clinical trial was designed to assess the activity of the combination of temsirolimus and bevacizumab in patients with recurrent or persistent endometrial carcinoma (EMC) [202]. 49 patients with a median age of 63 years with persistent or recurrent EMC after receiving 1 – 2 prior cytotoxic regimens, measurable disease, and Gynecologic Oncology Group performance status ≤ 2 were eligible for the trial. Majority of the patients had one prior chemotherapy regimen and 41% had received prior radiotherapy. The patients were given temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg every other week until disease progression or prohibitory toxicity [202]. The primary end points were progression-free survival (PFS) at six months and overall response rate using RECIST criteria [202]. Two gastrointestinal-vaginal fistulas, one grade 3 epistaxis, two intestinal perforations and 1 grade 4 thrombosis/embolism were reported. Three patient deaths reported were possibly treatment related. Twelve patients experienced clinical responses and 23 patients survived progression free for at least six months. The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 16.9 months respectively [202]. This combination therapy was deemed active based on both objective tumor response and PFS at six months in recurrent or persistent EMC [202]. However, this treatment regimen was associated with significant toxicity in this pretreated group. Future studies will be guided by strategies to decrease toxicity and increase response rates. Another study was conducted to evaluate the effectiveness of bevacizumab as a single agent in treatment of endometrial cancer. This study was a Gynecology Oncology Group Phase II trial (GOG 229-E)

4.7.4. Ovarian cancer Ovarian cancer is a cancerous growth that occurs in different parts of the ovary with majority arising from the epithelium of the ovary [206]. Ovarian cancers account for 5% of the total cancer deaths [206] and remains as the leading cause of death by gynecological malignancy worldwide [207]. About 58% of ovarian cancer cases occurrs in less developed countries. Fiji has the highest rate of ovarian cancer, followed by Latvia and Bulgaria [207]. According to the American Cancer Society, the overall 5-year and 10-year survival rates for ovarian cancer patients are 45% and 35% respectively [206]. Patients are usually diagnosed at an advanced stage and platinum-based systemic chemotherapy is recommended to most of the patients. However, some of the patients may develop platinum-resistant recurrent ovarian cancer and a 10–25% decrease of the response rate to chemotherapeutic agents are found in those patients [208]. Hence, antiangiogenic therapy has been explored in the management of ovarian cancers. Bevacizumab is the most widely studied of all the antiangiogenic agents in ovarian cancer [209]. Preclinical data have previously suggested that bevacizumab is beneficial as a first-line and maintenance therapy in the epithelial ovarian cancer (EOC) after cisplatin-based chemotherapy, by increasing the progression-free survival (PFS) [210,211]. Single agent of bevacizumab was found to be able to inhibit or delay the recurrence of the disease and prolong survival in a murine ovarian cancer model [211]. Majority of the investigations on using bevacizumab in the treatment of ovarian cancer are still in clinical trials and the results of the Phase II and III clinical trials are presented in Tables 3 and 4. 4.7.5. Phase II clinical trials Several authors namely, Fuh et al., Cannistra et al., and Burger 1136

70

36

13

52 42.3% 103 NA

Bevacizumab + Cyclophosphamide

Bevacizumab

Bevacizumab + Erlotinib

Bevacizumab + Irinotecan Bevacizumab +/-chemotherapeutic agent

1137 NA 21%

34

43

41

62

15

37

Bevacizumab + Pemetrexed

Bevacizumab + Liposomal doxorubicin

Bevacizumab + Paclitaxel (IV/IP) +Cisplatin (IP) Bevacizumab

Bevacizumab + Cyclophosphamide

Bevacizumab + Cyclophosphamide

NA

9 (20.9%)

14 (41%)

8 (20.5%)

22 (42.3%) NA

1 (7.69%)

6 (16.7%)

63% 50% 27.8% (for 6 months) 56%

PFS

38%

NA

24 (56%)

18 (53%)

NA

NA

56%

10 (25.6%) 31%

12 (23.1%) NA NA NA

7 (54%)

28 (77.8%) NA

44 (63%)

43 (18%) 2 (6%) 27 (25%)

SD

3 (8.1%)

12 (32.4%)

2 (13.3%) 6 (40.0%)

3 (8.1%)

3 (20%)

39%

18%

2 (3.29%) 11 (18.03%) 32 (51.6%) 40.3%

NA

4 (9.3%)

0

1 (2.6%)

0 NA

1(7.69%)

0

17 (24%)

15.9%

PR

4.5

4.4

4.7

28.6

7.8

7.9

4

8 NA

4.1

9.3

7.2

8.7 6.7 4.4

PFS median (months)

10.7

NA

16.9

NA

33.2

25.7

NA

13.8 NA

11

Not reached

16.9

14.3 10.5 10.7

4 diarrhea (26.67%) 1 pancreatitis (6.67%) No GIT perforation 1 intestinal fistulae (2.6%) No GIT perforation

6.5%

2%

36%

3.8% 19.5% (N&V) 12% (Bowel Obstruction) 12.5% No GIT perforation 15%

15%

0

4%

3% 6% 11%

OS (months) GI complication*

Adverse Effects

4%

NA NA 2.3%

VTE

5.3%

6.67%

9.7%

7%

46%

NA

7.5%

3.8% 19%

0

NA

7%

NA

0

0 NA

0

NA

4%

NA NA 0

Proteinuria (> grade 3)

2.7%

NA

NA

NA

3.23% 1.6%

NA

NA

NA

0

3.8% NA

0

13.9%(grade 3) NA

15%

36% 48% 9.1%

HTN

Burger et al. [174] Miyake, Sood, and Coleman [220] Pujade-Lauraine et al. [223]

Cannistra et al. [213] Garcia et al. [214] Brown et al. [215] Nimeiri et al. [216] Liu et al. [19] Robison et al. [217] Chambers et al. [218] Hagemann et al. [219] Pisano et al. [221] Oza et al. [222]

Fuh et al. [212]

References

Abbreviations: Pts, Patient; OR, overall response; CR, complete response; PR, partial response; SD, stable disease; PFS, progression free survival; OS, overall survival; GI, gastrointestinal; HTN, hypertension; VTE, venous thromboembolism; N&V, nausea and vomiting; GIT, gastrointestinal tract; NA: not available. * Majority - GIT perforation.

40.5%

53.3%

30.2%

41%

39

Bevacizumab + Erlotinib 23.1%

15.38%

16.7%

24%

0

244 37% 90 (37%) 33 21% 7 (21%) 44 7 (15.9%) 0

CR

Bevacizumab + Chemotherapeutic agent(s) Bevacizumab Bevacizumab

OR

Efficacy

Pts

Treatment

Table 3 Comparative findings of Phase II clinical trials using bevacizumab in the treatment of ovarian cancer.

D.K. Chellappan et al.

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625 623 484 764 179

Abbreviations: Pts, Patient; OR, overall response; CR, complete response; PR, partial response; SD, stable disease; PFS, progression free survival; OS, overall survival; GI, gastrointestinal; HTN, hypertension; VTE, venous thromboembolism; NA: not available. * Majority - GIT perforation.

0.7% 1.6% 8.5% < 1% 2% 5.3% 6.7% 4.0% 8% 3% 16.5% 22.9% 17.4% 18% 20% 2.8% 2.6% 1.6% 3% 2.2% 38.7 39.7 33.3 (data immature) NA 16.6 11.2 14.1 12.4 NA 6.7 NA NA NA 19% NA NA NA NA NA NA NA NA 21.1% NA NA NA NA 0 NA NA

PFS median (months) PFS SD PR CR

Bevacizumab + Paclitaxel+Carboplatin (initiation) Bevacizumab + Paclitaxel+Carboplatin (throughout) Bevacizumab+gemcitabine+carboplatin Bevacizumab+Carboplatin+Paclitaxel (maintenance) Bevacizumab + Paclitaxel/ Topotecan/ PEGylated liposomal doxorubicin

NA NA 21.1% NA 27.3%

GI complication* HTN OR

Pts Treatment

Table 4 Comparative findings of Phase III clinical trials using bevacizumab in the treatment of ovarian cancer.

OS (months)

Adverse effects Efficacy

VTE

Proteinuria (> grade 3)

References

Burger et al. [174] Burger et al. [174] Aghajanian et al. [203] Oza et al. [222] Pujade-Lauraine et al. [223]

D.K. Chellappan et al.

et al., had conducted Phase II clinical trials using bevacizumab as a single agent in the treatment of ovarian cancer. Both Fuh et al., and Burger et al have reported overall survival (OS) of 21% [212,213] in their studies but the study conducted by Cannistra et al only has 15.9% [213] of OS. The percentage of stable disease (SD) reported in all trials were also very different, and were 6% [212], 25% [213] and 51.6% [214] respectively. There were some similarities shown in progression free survival (PFS), which were 6.7, 4.4 and 4.7 months respectively [212–214]. The overall survival (OS) were only similar in the studies conducted by the former two, which were 10.5 and 10.7 months respectively [212,213]; while Burger et al had reported a higher OS of 16.9 months [214]. When it comes to adverse effects, all authors reported similar results on gastrointestinal complications, venous thromboembolism and proteinuria [212–214]. However, there is a significant difference in the number of cases of hypertension reported. Fuh et al reported that 48% of the patients suffered from hypertension during the treatment, but the other two studies reported that the incidents were five times lower [212–214]. Although the use of bevacizumab as an single agent is indeed effective in treating ovarian cancer, there were no trials which show similar trends in both its efficacy and adverse effects. Based on the studies conducted by Garcia et al., Chura et al., and Sanchez-Munoz et al., it can be speculated that the combination therapy of bevacizumab and metronomic oral cyclophosphamide is indeed effective in the treatment of recurrent or platinum-resistant ovarian cancer ([19,215,216], 2015b). Although all three studies reported that the combination therapy is helpful, the study conducted by Garcia et al., had reported cases of gastrointestinal tract (GIT) perforation and death ([19], 2015b), which was not found in the other two studies due to pre-treatment with chemotherapy before initiation of bevacizumab [217,218]. Hence, it is speculated that the risk of adverse effect of GIT perforation and death can be reduced by pre-treatment with chemotherapeutic regimen before initiating bevacizumab. However, the number of subjects in all studies were small. Hence, further investigations should be done to determine if the pre-treatment with chemotherapeutic agents before initiating bevacizumab can reduce the risk of such adverse effects. In another two studies conducted by Nimeiri et al., and Chamber et al., a combination of bevacizumab and erlotinib was used in treating ovarian cancer [219,220]. Both studies were shown to have very different results in terms of overall response, complete response, partial response and stable disease [219,220]. However, the progression free survival (PFS) in both studies were similar, with 38% and median of 4.1 months in the study conducted by Nimeiri et al; and a PFS of 31% with median of 4 months by Chamber et al., [219,220]. Both the studies showed no cases of venous thromboembolism and proteinuria and similar risks of gastrointestinal complication; except the case of hypertension, where 7.5% of the patients suffered from hypertension in the study conducted by Chamber et al., but no case was reported from Nimeiri et al., [219,220]. 4.7.6. Phase III clinical trials Four Phase III randomized clinical trials with combination therapy of bevacizumab along with a chemotherapeutic agent have been conducted. All the four studies reported that adding bevacizumab in the treatment was beneficial as there were improvements of progression free survival (PFS) [221]. However, there were only two studies conducted by Burger et al., and Oza et al., which were Gynecologic Oncology Group (GOG) 218 and ICON7 trials respectively, and which showed the benefit of overall survival (OS) among these patients [221]. GOG 218 and ICON7 studies have used bevacizumab in combination with standard chemotherapeutic agents (carboplatin + paclitaxel) in women who were newly diagnosed with ovarian cancer [221,222]. After the completion of six cycles of chemotherapy, bevacizumab was used as a maintenance therapy. Both of these studies showed an improvement in PFS [221,222].However, the study conducted by Burger 1138

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et al did not report any statistical difference in OS [221], while Oza et al reported a significant benefit of OS (8 months) in the group receiving bevacizumab as maintenance therapy [222]. An Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS) trial conducted by Aghajanian et al was aimed to compare the efficacy and safety of combination therapy using bevacizumab with carboplatin and gemcitabine in patients with relapse of platinum-sensitive ovarian cancer [211]. Aghajanian et al reported a statistically significant improvement in PFS of 4 months in patients who received bevacizumab [211]. Unfortunately, no benefit in OS was shown in this trial. On the other hand, the AURELIA trial involved the use of bevacizumab in platinum-resistant ovarian cancer patients [223]. Patients were randomized into two groups namely chemotherapy plus bevacizumab (CT + BEV) and chemotherapy (CT) alone [223]. The chemotherapy regimens included were liposomal doxorubicin, topotecan or weekly paclitaxel [223]. The result showed that combination of bevacizumab and chemotherapy had an increase in PFS of 3.3 months when compared to chemotherapy-only group [223]. Although there were benefits of using bevacizumab in ovarian cancer, there was also an increased risk of side effects such as hypertension, gastrointestinal complications and proteinuria [165,211]. The selected adverse events observed in 4 Phase III randomized trials have been summarized in Table 4. The adverse events reported varied according to the treatment regimens. Overall, hypertension was reported as the most common adverse event in all these phase trials [211,223]. The OCEAN trial has shown an unexpected high incidence of proteinuria but majority of the hypertension and proteinuria that occured in the trial were resolved well [211]. Both GOG 218 and ICON 7 trials showed that there was only a slight increase in the risk of gastrointestinal tract (GIT) perforations in patients treated with combination of bevacizumab with chemotherapeutic agent [223]. On the other hand, there were no GIT perforation events in the platinum-sensitive patients in OCEAN trials [211] and only 2% in platinum-resistive patients AURELIA trials [223]. Bevacizumab is believed to be effective in the treatment and management of ovarian cancer [224,225]. However, it shows varied results based on its use as a single agent [226,227] and when it was combined with other chemotherapeutic agents [165,211,223]. After the approval by FDA, and based on the positive results documented in both Phase II and Phase III clinical trials [165], the effectiveness of bevacizumab in the treatment and management of solid tumors was widely appreciated, and hence there is a strong reason for using bevacizumab in the management of ovarian cancers.

been widely used in the treatment and management of various cancers especially solid tumors and in recent years, gynecological cancers. Bevacizumab is proven to have a very high potential in the treatment of gynecological cancers. Results from various studies conducted in gynecological cancers showed promising results where this antiangiogenic agent is really effective in reducing the size of the tumor through the inhibition of VEGF production. The effectiveness of bevacizumab is indicated by the increased overall survival (OS) and progression free survival (PFS) in terms of months. In Phase II and Phase III clinical studies conducted for cervical cancer, bevacizumab was proven to be effective in improving the OS and PFS of cervical cancer patients. However, the results showed that the use of bevacizumab in combination with chemotherapeutic agents had a higher OS and PFS when compared to bevacizumab alone. On the other hand, the effectiveness of bevacizumab to treat endometrial cancer was proven through only a handful of clinical trials. The result showed that this antiangiogenic agent did help to slow down the progression of endometrial cancer when used as a combination with chemotherapeutic agents or radiation therapy. Several adverse effects were also seen in trials for these cancers, which are related to gastrointestinal and hematological system. The studies with bevacizumab in the treatment of ovarian cancers suggested that bevacizumab should be the first line treatment and maintenance therapy for epithelial ovarian cancer. When it comes to the adverse effects reported in ovarian cancer patients, the majority of the adverse effects reported were hypertension, venous thromboembolism, gastrointestinal complications and proteinuria; whereby the most common one being hypertension. In general, bevacizumab was proved to be effective in the treatment of gynecological cancers based on the increased OS and PFS. Furthermore, the combination of bevacizumab and chemotherapeutic agents were shown to have higher OS and PFS when compared to bevacizumab as a single agent, which suggested that the combination therapy is more effective in improving the prognosis of the cancer, especially endometrial cancers. However, the cost of bevacizumab therapy is relatively higher when compared to chemotherapy or radiation therapy. Hence, more studies regarding the cost-effectiveness of bevacizumab in gynecological cancers should be conducted to get a better evaluation for balancing the social burden and also determine the best possible therapy for those in need.

5. Conclusion

Conflict of interest

Disclosure The authors report no conflicts of interest in this work.

In the treatment of gynecological cancers, surgery was one of the most trusted therapies in the early stages, whereas radiation therapy was used in the later stages. However, for patients with advanced gynecological cancers, the availability of newer treatments will be very crucial because the existing treatment options are very limited. The treatment options become more complicated when associated with poor prognosis along with problems such as resistance to chemotherapeutic agents. Angiogenesis is quoted as the culprit behind the worsening prognosis in such patients as this process enhances the formation of new blood vessels and allows tumor to gain nutrients and oxygen supply for their growth and hence, leads to metastasis. The physiological imbalance between the proangiogenic and antiangiogenic factors, whereby proangiogenic factors such as vascular endothelial growth factors (VEGF) predominate is found to be the key factor behind the manifestation of angiogenesis. Therefore, novel therapeutics in cancer therapy now focuses on the development of agents which specifically target these proangiogenic factors in order to slow down or halt angiogenesis. Bevacizumab is one of the antiangiogenic agents that has

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