Description of the condition

Cervical cancer is the second most commonly diagnosed cancer affecting women worldwide and the third leading cause of death from cancer among women in low‐income countries (Bray 2018; Ferlay 2019; Siegel 2019). Almost 70% of the global burden falls on low‐ and middle‐income countries, in which 9 out of 10 cervical cancer deaths occur (Ferlay 2019). A woman's risk of developing cervical cancer before the age of 74 years is estimated to be 1.36% worldwide, ranging from 0.9% in more developed to 1.6% in less developed areas (Ferlay 2019; Torre 2015). The World Health Organization (WHO) recognises three pathological types of cervical cancer, including squamous cell carcinoma (70% to 80%), adenocarcinoma (20% to 25%), and other types (adenosquamous carcinoma, neuroendocrine tumour, and undifferentiated carcinoma) (Marth 2017). Since the introduction of cytology‐based cervical screening, the incidence and mortality rates of cervical cancer have been reduced by approximately 75% in countries with co‐ordinated population vaccination and screening programmes (Cancer Research UK 2014; ISD Scotland 2011; Siegel 2019; Welsh Cancer Intelligence and Surveillance 2011). A majority of cervical cancer cases (60%) are associated with inadequate screening and therefore are potentially preventable, or cervical cancer may be diagnosed at a very early stage, remaining easily curable with surgery (Alldredge 2016; Eskander 2014; Rebolj 2019). However, even in women diagnosed at a relatively early stage who have undergone treatment with surgery or radical chemoradiotherapy, the risk of recurrence is 10% to 20% for stages IB to IIA, and 28% to 64% for locally advanced FIGO stages IIB to IV, as per the classification of the International Federation of Obstetrics and Gynaecology (FIGO) (see Figure 1 for FIGO cervical cancer staging 2018) (Bhatla 2018; Bhatla 2019; Bray 2018; Cancer Research UK 2014).

Figure 1

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FIGO stage 2018 (with correction Bhatla 2018; Bhatla 2019).

Early‐stage cancer (FIGO stages IA, IB1, IB2, and IIA1) can be treated by surgery or chemoradiotherapy (Bhatla 2018; Bhatla 2019; Marth 2017; NCCN 2018). For locally advanced disease (FIGO stages IB3 to IVA), standard treatment is concurrent platinum‐based chemoradiotherapy, such as weekly cisplatin, during radiotherapy (Bhatla 2018; Bhatla 2019; Marth 2017; NCCN 2018). In general, five‐year survival rates are 99% for stage IA1 and 98% for stage IA2; for stages IB to IIA, five‐year survival rates are 88% to 95% without lymph node metastasis, and 51% to 78% with lymph node metastasis; for stage IIB, the rate is 65%, for stage III 40%, and for stage IV 10% to 20% (Cao 2014; Kim 2000). Very advanced cervical cancer (FIGO stage IVB), in which the disease has spread to areas outside of the pelvis upon diagnosis (distant metastatic disease), has a very poor prognosis. Treatment options are limited and are unlikely to be curative; therefore management is aimed at prolonging life and managing symptoms. Similarly, in recurrent disease, unless exenterative surgery is possible, women usually are treated with palliative chemotherapy. Chemotherapy aims to prolong survival, provide symptom control, and improve quality of life. For women not medically fit enough for chemotherapy, treatment options in both metastatic and recurrent disease may be limited to at best supportive care, with the option of palliative radiotherapy, if appropriate (Eleje 2019; Fanfani 2016; Greer 2010; Matsuo 2015; Waggoner 2003).

Persistent, recurrent, and metastatic diseases are the main causes of death among women with cervical cancer (Scatchard 2012). In persistent disease, visible lesions appear within six months of primary surgery, or within three to six months of completion of primary radiotherapy; in recurrent disease, visible lesions appear within an interval of more than six months after primary surgery, or within three to six months of completion of primary chemoradiotherapy (Cao 2011). More than 60% of recurrent diseases are detected within two years of primary treatment, and about 10% are detected after five years (Cao 2011). Persistent or recurrent cancers occur in about 35% of women with stages IB to IIA disease, and in 50% to 70% of patients with stages IIB to IVa disease; if cancer recurs, five‐year survival rates drop to 5% to 10% (Arbyn 2020; Cao 2017; Cao 2019). More than 60% of recurrent disease occurs in the pelvic cavity, including the central pelvic cavity (uterine cervix, vagina, and uterine body), parametrium, and pelvic side wall (Cao 2014). Women who experience distant metastases (i.e. cancer that has spread from the original (primary) tumour location to distant organs or distant lymph nodes, outside of the pelvis), either upon initial diagnosis (FIGO stage IVB) or at the time of recurrence, will have a poor prognosis. In recurrent disease, metastatic rates (16% to 31% for IB and IIA, 26% for IIB, 39% for III, and 75% for IVA) increase with FIGO stage (Cao 2017). Sites of distant metastatic disease often include the lungs (21%), bone (16%), the para‐aortic region (11%), the abdominal cavity (8%), and the supraclavicular region (7%) (Cao 2014). Three phase 3 randomised trials (GOG‐204, GOG‐240, and Japanese Clinical Oncology Group 0505 (JCOG‐0505)) have examined chemotherapy regimens for women with advanced and recurrent cervical cancer (Monk 2009a; Saito 2010; Tewari 2014). The main concern was acquired resistance to platinum‐based chemotherapy in individuals with recurrent cervical cancer who were previously treated with chemotherapy. However, regimens that did not include a platinum agent were not found to be superior to cisplatin‐based treatments; therefore cisplatin plus paclitaxel remains the chemotherapy standard for recurrent and metastatic disease (Eleje 2019; Monk 2014).

Angiogenesis inhibitors are a class of promising biological agents that target the process by which a tumour forms new blood vessels to supply it with oxygen and nutrients. This process is key to the growth of cervical cancer, both locally and in metastatic deposits (Willmott 2009). In 1971, Folkman proposed a tumour angiogenesis‐dependent doctrine, which suggested that the development of tumours was due to the ability of individual cancer cells to grow without normal controls but was also dependent on the nutrient and oxygen supply via blood vessels (Folkman 1971). The transition of a tumour from an avascular to a vascular phase was termed the 'angiogenic switch' and was thought to be an important factor in the clinical progression from tumour dormancy to cancerous invasion (Hanahan 1996). The angiogenic switch occurs through a dynamic process involving pro‐angiogenic and anti‐angiogenic factors that are normally maintained in balance (physiological homeostasis). Cancer is characterised by up‐regulation of pro‐angiogenic factors, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet‐derived growth factor (PDGF), and angiopoietins, and down‐regulation of anti‐angiogenic factors, such as thrombospondin, angiostatin, and endostatin, leading to the development of new blood vessels (neovascularisation) and tumour progression (Hicklin 2005). Neovascularisation is therefore a vital process in metastatic spread, which allows malignant cells to enter into the circulation (Falzone 2019; Folkman 1971; Folkman 1990; Pfaendler 2016). Activation of VEGF promotes the proliferation and migration of endothelial cells, which form the lining of blood vessels, and the development of new blood vessels. Moreover, VEGF activation enhances the leakiness (permeability) of existing blood vessels and consequently causes increased leakage of multiple plasma proteins that are involved in the angiogenesis process (Nagy 2007; Turajlic 2018). These proteins are ligands to three VEGF receptors (VEGF‐R1 to ‐R3) and are responsible for initiating a cascade of reactions that promote the migration, proliferation, and survival of endothelial cells, leading to the formation of new blood vessels. VEGF‐R1 and VEGF‐R2 are responsible for the regulation of angiogenesis, whereas VEGF‐R3 plays a secondary role in angiogenesis but is essential for lymphangiogenesis (development of new lymphatic vessels) and therefore is involved in the production of ascites and lymphatic dissemination of metastatic factors (Ellis 2008). Angiogenesis is present in pre‐malignant conditions of the cervix, as well as in invasive disease, which can be seen at colposcopy with the occurrence of vascular changes. Studies have shown that microvessel (small vessel) density increases progressively with the grades of cervical intraepithelial neoplasia (CIN), suggesting that angiogenesis may be an early event in the development of cervical pre‐cancer and cancer (Dobbs 1997; Guidi 1994; Krill 2015; Smith‐McCune 1994). Cervical cancer has been shown to be more dependent on angiogenesis than most other solid cancers because human papillomavirus (the cause of almost all cervical cancers) and hypoxia, with increased hypoxia‐inducible factor 1 alpha, are associated with higher levels of VEGF (Monk 2009b). In addition, increased intratumoural microvessel density during histological examination and enhanced expression of proteins, such as the endothelial antigen CD31, have been associated with a poor prognosis (Dellas 1997; Dobbs 1997; Tjalma 1999). Targeting the cancer microenvironment, specifically, new blood vessel formation, using VEGF pathway inhibition is the main goal of inhibition of angiogenesis.

Description of the intervention

Angiogenesis, the development of new blood vessels, is essential for initiation of tumours, their growth, and metastasis (Tan 2010). Tumours require angiogenesis to receive enough nutrients and oxygen to grow beyond 1 to 2 mm in diameter and to facilitate metastasis (Wagner 2009). The process of tumour‐related angiogenesis is regulated by various pro‐angiogenic factors, such as VEGF, and their cognate receptors, which are the dominant regulators of the proliferation of endothelial cells and the formation of new blood vessels (Tan 2010). VEGF acts by binding to its receptor, which then signals within the cell via tyrosine kinase enzyme activity (tyrosine kinases). VEGF‐R1 (Flt‐1 or fms‐like‐tyrosine kinase) and VEGF‐R2 (KDR/flk‐1) belong to the best characterised angiogenesis signalling pathway, and they can be blocked by inhibitors, such as antibodies (bevacizumab) or soluble receptors, which bind to VEGF and prevent it from binding to its receptors on cells. VEGF‐R2 is thought to be the dominant receptor responsible for translating and regulating angiogenesis (Bellone 2007).

Unlike chemotherapy agents that attack tumour cells, angiogenesis inhibitors are developed to block VEGF signalling pathways (Jayson 2016). This was first shown in 1993, when anti‐VEGF monoclonal antibodies were found to exert a potent inhibitory effect on the growth of three tumour cell lines injected subcutaneously into mice (Kim 1993). It is interesting to note that the antibody had no effects on cell lines in vitro. However, several parallel studies confirmed in vivo growth inhibition, which correlated with decreased tumour microvessel density and inhibition of tumour angiogenesis (Borgstrom 1996; Borgstrom 1998; Borgstrom 1999). It is now known that VEGF targeting agents ‐ angiogenesis inhibitors ‐ starve the tumour by preventing the formation of blood vessels and inhibit the growth and spread of tumours. VEGF targeting agents have been tested in some solid tumours, including metastatic colorectal cancer, metastatic thyroid cancer, ovarian cancer, high‐grade glioblastoma, and endocrine refractory or resistant metastatic breast cancer (Gaitskell 2011; Khasraw 2014; Tan 2010; Wagner 2009; Wagner 2012).

Phase 1 to 3 clinical trials of some VEGF targeting agents (bevacizumab, cediranib, pazopanib, sunitinib, and sorafenib) have been completed in women with persistent, recurrent, metastatic, and locally advanced cervical cancer (Mackay 2010; Milosevic 2016; Monk 2009a; Monk 2010; Schefter 2014; Symonds 2015; Tewari 2014; Zighelboim 2013). Bevacizumab is a humanised monoclonal antibody directed against all major isoforms of VEGF (VEGF‐A, VEGF‐B, VEGF‐C, VEGF‐D, placental growth factor (PIGF), VEGF‐E, and VEGF‐F members). It is used extensively in the USA and is the most studied biological agent in gynaecological cancer (Grothey 2009; Tewari 2014). Several published randomised controlled trials (RCTs) and non‐randomised trials have reported binding and inactivation of VEGF through the clinical use of bevacizumab as a single agent (Monk 2009a; Monk 2009b; Schefter 2012; Schefter 2014; Takano 2013; Tan 2010; Tewari 2005; Tewari 2014; Tewari 2014b; Wright 2006). It has now been approved in more than 60 countries for the treatment of persistent, recurrent, or metastatic disease, in combination with paclitaxel and cisplatin, or paclitaxel and topotecan, based on improved overall survival (OS) with typical adverse events (hypertension, thromboembolic events, and gastrointestinal fistulae) in the Gynecologic Oncology Group (GOG)‐240 trial (Tewari 2017).

The treatment plan for persistent, recurrent, or metastatic cervical cancer depends on the performance status of the person with cancer (i.e. his or her general well‐being), the disease site, the extent of disease, and previous treatment (Bhatla 2018; Bhatla 2019). For women with isolated distant metastasis or locoregional recurrence (i.e. original microscopic cancer cells that have resisted primary therapy and become visible at the original site), treatment includes individualised radiotherapy (external radiation or brachytherapy (intracavity radiotherapy), or both), with or without cisplatin chemotherapy; surgical resection can be used for control of local disease and symptoms (NCCN 2018). For women with central pelvic recurrence after primary radiotherapy, pelvic exenteration (i.e. removal of part or all of the pelvic organs), with or without intraoperative radiotherapy, may be considered. Surgical mortality rates of less than 5% and long‐term survival rates of approximately 50% have been reported (Morley 1989). Radical hysterectomy or brachytherapy may also be considered, if the central pelvic lesion is small (< 2 cm) and isolated (NCCN 2018). For women with extrapelvic metastases or recurrences who are unsuitable to undergo surgery or radiotherapy, combination cisplatin‐based chemotherapy regimens are often recommended (i.e. paclitaxel and cisplatin combined with bevacizumab) over the use of single agents (NCCN 2018). However, overall response rates to chemotherapy are about 20% (15% to 46%), with median OS of six to eight months and median progression‐free survival (PFS) of three months (Marth 2017; Moore 2006; Tewari 2005).

How the intervention might work

Over‐expression of VEGF has been found in most human cancers compared with normal tissues (Jayson 2016). VEGF is released by tumour cells and interacts with its receptor (VEGF‐R), a transmembrane protein, on the nearby endothelial cells of normal blood vessels (see Gaitskell 2011 for figures describing receptor function). VEGF binds to the extracellular domain of VEGF‐R, stimulates tyrosine kinase activity in the intracellular domain of VEGF‐R, and triggers the downstream network of cell signalling pathways that promote the proliferation of endothelial cells and the formation of new blood vessels (Kerbel 2008). VEGF and VEGF‐R have already become the dominant targets for clinical angiogenesis inhibitors (Jayson 2016). VEGF signalling pathways can be blocked by several mechanisms, including VEGF blockades (e.g. anti‐VEGF antibodies (bevacizumab), VEGF‐trap (aflibercept)), VEGF‐R blockades (e.g. anti‐VEGF‐R antibodies (ramucirumab)), and interruption of intracellular signalling pathways (e.g. tyrosine kinase inhibitors (TKIs) cediranib, pazopanib, sorafenib, sunitinib) (Alldredge 2016). Results of xenograft models of human tumours in mice have shown that VEGF targeting agents cause regression of microvascular tissues and reduction in metastatic disease progression (Genentech 2020; Morton 2012).

Bevacizumab (Avastin) is a VEGF‐directed antibody that has been given as an intravenous infusion as monotherapy or with other therapies to treat cervical cancer in clinical trials. In a phase 2 study of 46 women with persistent or recurrent squamous cell carcinoma, single‐agent bevacizumab was active and well tolerated. Median OS was 7.29 months, and median PFS was 3.40 months, with common severe adverse events of hypertension, thromboembolic events, and gastrointestinal disorders (Monk 2009a). In a phase 2 study of 27 women with persistent or recurrent disease (66.6% were squamous), bevacizumab was used with cisplatin and topotecan, median OS was 13.2 months, and median PFS was 7.1 months. However, severe haematologic toxicities were common, including thrombocytopenia, leukopenia, anaemia, and neutropenia. Most of the women required at least one unexpected hospital admission for supportive care (Zighelboim 2013). In a phase 2 study of 49 women with locally advanced disease (63% were IIB, 80% were squamous), bevacizumab (10 mg/kg every 14 days for three cycles) was used with concurrent platinum‐based chemoradiotherapy; three‐year OS and PFS rates were 81.3% and 68.7%, respectively, and no significant treatment‐related adverse events occurred (Schefter 2014). In a GOG‐240 phase 3 study of 452 women with persistent, recurrent, or metastatic cervical cancer (68.6% were squamous), participants were randomised to receive bevacizumab with chemotherapy (paclitaxel and cisplatin, or paclitaxel and topotecan) or chemotherapy alone. The addition of bevacizumab to chemotherapy improved median OS to 17.0 months versus 13.3 months, and median PFS to 8.2 months versus 5.9 months, compared with chemotherapy alone. However, adverse events, including hypertension, severe thromboembolic events, and severe gastrointestinal fistulae, were increased (Tewari 2014).

Cediranib (Recentin) is a small molecule TKI of VEGF‐R. In a phase 2 study of 69 women with metastatic or recurrent disease, participants were randomised to receive cediranib with chemotherapy (paclitaxel and carboplatin) or chemotherapy alone. The addition of cediranib to chemotherapy improved median PFS as compared with chemotherapy alone (8.1 months versus 6.7 months) but did not improve median OS (13.6 months versus 14.8 months); adverse events, including hypertension, febrile neutropenia, and diarrhoea, were increased (Symonds 2015).

Pazopanib (Votrient) is an oral multi‐targeted TKI of VEGF‐R, a platelet‐derived growth factor receptor (PDGF‐R), and c‐kit. Lapatinib is an oral dual TKI of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/neu). In a phase 2 study of 228 women with persistent, recurrent, or metastatic cervical cancer, participants were randomised to receive single‐agent pazopanib (800 mg once daily), single‐agent lapatinib (1500 mg once daily), or pazopanib plus lapatinib (this arm was terminated due to toxicity). Pazopanib improved median OS (50.7 weeks versus 39.1 weeks) and PFS (18.1 weeks versus 17.1 weeks) as compared with lapatinib; the most common adverse events were similar in both groups: diarrhoea, nausea, hypertension, and anorexia (Monk 2010).

Sunitinib (Sutent) is an oral multi‐targeted TKI of VEGF‐R, PDGF‐R, and c‐kit. In a phase 2 study of 19 women with incurable locally advanced or metastatic disease, single‐agent sunitinib was administered in a six‐week cycle for up to a maximum of six cycles; no tumour response was observed during follow‐up (median 4.4 months), and five cases of fistula formation were observed (Mackay 2010).

Sorafenib (Nexavar) is an oral multi‐targeted inhibitor that targets both VEGF‐R and PDGF‐R tyrosine kinase and Raf serine/threonine kinase. In a phase 1 study of 13 women with locally advanced disease, sunitinib was administered before and during concurrent platinum‐based chemoradiotherapy, but the study was terminated after a preliminary analysis because sorafenib increased tumour hypoxia, which is a strong predictor of disease progression (Milosevic 2016).

Why it is important to do this review

Increasing knowledge about the molecular biology of gynaecological cancers has led to the development of biological therapies. Treatment options for persistent, recurrent, and metastatic cervical cancer are limited, and the purpose of current treatment is to relieve symptoms and improve quality of life (Bhatla 2018; Marth 2017; NCCN 2018). Other agents have not shown a survival advantage compared with standard therapy (Marth 2017; NCCN 2018). However, a phase 3 clinical trial showed that the addition of bevacizumab to chemotherapy improved survival from 13.3 months to 16.8 months (Penson 2015; Tewari 2014; Tewari 2017). Since publication of the early results of Tewari 2014, bevacizumab has become the standard of care in combination with chemotherapy for individuals with metastatic and recurrent cervical cancer in some high‐income countries (Genentech 2020). Other anti‐angiogenic agents have been studied to a lesser degree than bevacizumab.

Cochrane Reviews of VEGF targeting therapy have been produced for glioma and for thyroid, ovarian, colorectal, and breast cancers (Gaitskell 2011; Khasraw 2014; Tan 2010; Wagner 2009; Wagner 2012). Clinical trials have shown that VEGF targeting agents improved OS or PFS but increased tolerable toxicities among women with persistent, recurrent, or metastatic cervical cancer (Monk 2010; Symonds 2015; Tewari 2014). This Cochrane Review aims to assess the benefits and harms of VEGF inhibitors alone or in the adjuvant setting for treatment of persistent, recurrent, or metastatic cervical cancer, with the goal of assisting clinicians and women involved in the decision‐making process.