Anti-Angiogenesis Therapy in Gynecologic Malignancies

May 15, 2015

The purpose of this paper is to provide a review of site-specific treatment options that involve the targeting of angiogenesis in gynecologic malignancies.

Anti-angiogenic agents are an important adjuvant treatment strategy in gynecologic cancer. Bevacizumab was recently approved for use in advanced cervical cancer and platinum-resistant ovarian cancer. The overall survival advantage bevacizumab confers in advanced cervical cancer prompted a paradigm shift in the standard of care for this disease. Because many other therapeutic options are available, and because of the heterogeneity of ovarian malignancies, the best combination of chemotherapeutics and bevacizumab has yet to be determined; studies are on-going. The utility of bevacizumab in uterine cancer has not been consistently demonstrated; current studies are limited to early-phase clinical trials. Other anti-angiogenic agents, including oral therapies for cervical and ovarian cancers, are under investigation; this therapeutic class of drugs appears promising.


Each year, more than 91,700 new cases of gynecologic malignancies are diagnosed in the United States, and more than 28,000 women lose their lives to gynecologic cancer.[1] Until recently, treatment paradigms in gynecologic oncology have mainly included a combination of radical surgery, cytotoxic chemotherapy (CT), and radiation therapy. Angiogenesis, the recruitment of new blood vessels from the pre-existing vascular matrix, is now a well-established prerequisite for tumor progression. Growth factors such as fibroblast growth factor (FGF), vascular endothelial cell growth factor (VEGF), and angiopoietin-1 (Ang1) are upregulated to stimulate angiogenesis, while downregulation of endogenous protein inhibitors (thrombospondin 1 and interferon) disrupts the balance of physiologic angiogenesis. These events are influenced by and activate other molecular pathways, including phosphatidylinositol 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK),[2] and therapies are now available that target these pathocellular processes.

The past year saw the approval of the humanized anti-VEGF antibody bevacizumab for two indications in gynecologic oncology. In August 2014, the US Food and Drug Administration (FDA) approved bevacizumab for the treatment of advanced cervical cancer, the first gynecologic cancer for which an anti-angiogenic agent has demonstrated an advantage in overall survival (OS). In November 2014, recurrent platinum-resistant ovarian cancer became an approved indication for bevacizumab. Cervical and ovarian carcinogenesis employ different pathways to achieve cellular immortalization, and this has a significant bearing on the evidence supporting the use of anti-angiogenic agents in the two malignancies. The use of anti-angiogenesis in uterine cancer is currently still undergoing more basic investigation, with clinical trials in earlier stages. The purpose of this paper is to provide a review of site-specific treatment options that involve the targeting of angiogenesis in gynecologic malignancies.

Targeting the angiogenesis pathways

In the last 8 decades, theories regarding carcinogenesis have progressed to include numerous pathways by which cells achieve immortality. Growing evidence suggests that the interaction between the genomic/epigenomic aberrations in cancer cells and the surrounding microenvironment, composed of immune and stromal cells, contributes to the development of tumor invasion via mechanisms such as the so-called “angiogenic switch,”[3-5] creating multiple opportunities for therapeutic intervention.

Angiogenesis has been studied in depth, with the VEGF pathway having received the most attention because of its central role in regulation. However, multiple pathways are currently under investigation and hold tremendous promise for the future treatment of gynecologic malignancies (Figure 1). Therapeutic targets from these pathways are desired because agents that target them are often well tolerated in the treatment setting and may work synergistically with cytotoxic CT.[6] VEGF-A (also known as VEGF) has a potent effect on proliferating endothelial cells by activating the C-Raf–MAPK/ERK kinase (MEK)–extracellular signal-regulated kinase (ERK) pathway and preventing apoptosis via activation of Akt through the PI3K pathway.[7,8] The VEGF-dependent axis may be targeted extracellularly, via bevacizumab or ziv-aflibercept (the latter a recombinant fusion protein of human immunoglobulin G1 and the extracellular domains of VEGF receptor 1 [VEGFR1] and VEGF2); this axis may also be targeted intracellularly, via inhibition of tyrosine kinases of VEGFR. These tyrosine kinase inhibitors (TKIs)-eg, pazopanib, cediranib, and nintedanib-are oral agents and have had encouraging results in phase II/III trials in gynecologic cancers.

The angiopoietin/Tie pathway consists of two tyrosine kinase receptors (Tie1, Tie2) and three ligands (Ang1, Ang2, and Ang4), and provides an important link between the angiogenic and inflammatory pathways. Ang1 functions as a Tie2 receptor agonist, stabilizing endothelial junctions, while Ang2 normally functions as an Ang1 antagonist, promoting endothelial sprouting and vascular permeability; both Ang1 and Ang2 increase blood vessel density.[9] Trebananib (AMG-386) is a peptide-Fc fusion protein that binds Ang1 and Ang2, preventing their interaction with the Tie2 receptor. TRINOVA-1 (Trebananib in Ovarian Cancer 1) is a phase III trial that randomly assigned women with recurrent ovarian cancer to receive weekly paclitaxel either with or without trebananib (Table-PDF).[10] The study met its primary endpoint of progression-free survival (PFS), with a significant improvement in the trebananib arm relative to the control arm (7.2 vs 5.4 months; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.57–0.77; P < .001). Trebananib plus carboplatin and paclitaxel chemotherapy (CT) as first-line treatment for advanced ovarian cancer is currently being evaluated in TRINOVA-3 (NCT01493505), which recently closed to accrual.

Platelet-derived growth factor (PDGF) and FGF are parts of another key regulatory pathway in angiogenesis. PDGF binds PDGF receptor β (PDGFR-β), which stimulates pericyte recruitment and blood vessel maturation.[11] The FGF family activates angiogenesis via interaction with FGF receptor 1 (FGFR1) and FGFR2,[12] and inhibition of these alternate pathways (PDGF, FGF) may mediate resistance and potentiate VEGF inhibition, supporting a multitargeted approach.[13-15] Most TKIs used in clinical trials circumvent the possible PDGF-induced resistance to anti-VEGF therapy by employing a multitargeted approach, inhibiting both VEGFR and PDGFR, among others (eg, cedirinib, sorafenib, nintedanib, sunitinib, and pazopanib).

The epidermal growth factor (EGF) pathway is another potential target in the angiogenesis pathway. It consists of the EGF receptor (EGFR; also known as ErbB1 and HER1), in addition to the well-known tyrosine kinase subfamily consisting of HER2/neu, HER3, and HER4. EGFR dimerization elicits downstream activation of several signal transduction cascades, principally the MAPK/Akt/c-Jun N-terminal protein kinase (JNK) pathways, leading to DNA synthesis and cell proliferation.[16,17] In xenograft models, EGFR inhibition was associated with higher levels of VEGFR2 microRNA (mRNA) and protein, suggesting that EGFR may generate resistance to anti-VEGF therapy. A small-molecule inhibitor of VEGFR and EGFR, vandetanib, was created to address EGFR-mediated anti-VEGF resistance and is currently under investigation in combination with docetaxel for recurrent ovarian cancer (NCT00872989).

The hepatocyte growth factor (HGF) ligand receptor tyrosine kinase, also called c-MET, has been implicated in epithelial malignancies, including epithelial ovarian cancer (EOC).[18] The HGF/c-MET axis is responsible for the cell-scattering phenotype and increases angiogenesis by promoting growth, movement, and morphogenesis of endothelial cells via downstream stimulation of pro-angiogenic pathways, including PI3K/Akt and Src. Experiments with c-MET inhibition in vivo have been shown to decrease peritoneal dissemination of ovarian cancer cells and to inhibit ascites formation.[19] Rilotumumab, a monoclonal HGF antibody, is currently undergoing phase II investigation for recurrent EOC (NCT01039207).

Another family of receptor tyrosine kinases that regulates pathologic angiogenesis is the Ephrin/Eph receptor pathway.[20] The relevant feature of these receptor tyrosine kinases is their ability to mediate contact-dependent cell-cell communication, and mutations in this system have been associated with cancers. The downstream effects of Eph receptor signaling include activation of integrins and other focal adhesion–associated proteins. Although a specific role in carcinogenesis has not been clarified, the role of Eph receptors in intercellular communication is likely their contribution to the cancer–somatic cell interface of the tumor microenvironment and represents another potential therapeutic target.

The Delta 4 (Dll4)/Notch signaling pathway is another target for new biologic therapies. Notch proteins are cell surface protein receptors normally involved in transmitting growth signals to those cells undergoing physiologic cell fate changes. In the angiogenic cancer microenvironment, they have been associated with vessel maturation, pericyte recruitment, and vascular branching. The Notch pathway has also been implicated in the physiologic response to loss of VEGF signaling, and thus may participate in tumor adaptation to VEGF inhibitors.[21,22] Currently, a phase II trial evaluating RO4929097, an oral gamma secretase inhibitor, is being evaluated in platinum-resistant recurrent ovarian cancer (NCT01175343). A combined approach using inhibition of both Notch and VEGF may hold promise in the future treatment of patients with gynecologic cancers.

The Src nonreceptor kinase family directly interfaces with the VEGF axis and plays an important role in cell adhesion and survival in both normal cells and cancer cells. Upon VEGF-A binding to VEGFR1/VEGFR2 in vascular endothelial cells, the intrinsic tyrosine kinase activity of these receptors leads to transphosphorylation and direct interaction with Src, which goes on to activate vascular endothelial–cadherin and to induce conformational changes in the endothelial cytoskeleton and tumor microenvironment.[23] Currently, two Src kinase family inhibitors, dasatanib (NCT00671788, NCT00788125, NCT00672295) and saracatinib (NCT00610714, NCT01196741, NCT00475956), are being studied in phase I/II clinical trials in advanced ovarian cancer and may be advanced into the phase III arena.

The PI3K/Akt/mTOR signaling cascade is one of the most important intracellular pathways involved in carcinogenesis.[24] mTOR is a serine/threonine kinase and central regulator of ribosome function residing downstream from the PI3K/Akt pathway.[25,26] mTOR is hypothesized to interact with the VEGF pathway via actions carried out by its two distinct complexes, mTOR complex 1 (mTORC1) and mTORC2, whose downstream effects also play a role in lipid and protein synthesis and energy metabolism.[27,28] Falcon et al showed a combination of mTORC1/mTORC2 and VEGF inhibition decreased tumor growth in xenograft models more than either inhibitor alone.[28] Additionally, Akt is important for endothelial cell survival when new vessels are formed. Everolimus, an mTOR inhibitor, has been studied in multiple phase II trials in gynecologic malignancies.

Finally, vascular disrupting agents (VDA), a class of tubulin destabilizers and flavonoids, are some of the newest non-chemotherapeutic options; VDAs target aberrant vascularization and are being studied in the setting of ovarian cancer. While agents like bevacizumab target the recruitment of new vasculature to the periphery of tumors, VDAs act at the level of endothelial cells to limit tumor perfusion, causing tumor necrosis from within. Results from Gynecologic Oncology Group (GOG) 186I (NCT01305213), a phase II trial utilizing the VDA fosbretabulin tromethamine in combination with bevacizumab in patients with recurrent or persistent ovarian cancer, were recently presented at the International Gynecologic Cancer Society 2014 Annual Meeting. The antivascular/anti-angiogenesis combination was associated with an improved response rate and PFS, but hypertension rates were doubled. The avoidance of side effects commonly associated with cytotoxic chemotherapy makes this an attractive alternative for this patient population.

Endometrial Cancer

Affecting 49,560 women yearly, endometrial cancer is the most common gynecologic malignancy in the United States.[1] The majority of cases are diagnosed at an early stage; however, effective treatment options for advanced endometrial cancer are limited. Anti-angiogenesis agents may be uniquely capable of filling that therapeutic void. Angiogenesis has a distinctive role in the endometrium, responding to the hormonal changes of the menstrual cycle with alternating proliferation and decidualization.[29,30] Hypoxia and sex steroids have been shown to influence expression of both Ang1 and VEGF microRNA (mRNA) in the endometrium.[31] Treatment with medroxyprogesterone acetate has also been associated with a reduction in VEGF and FGF in well-differentiated endometrial cancer. [30] The majority of endometrial cancers have aberrant phosphatase and tensin homolog (PTEN) activity, which engages multiple angiogenesis pathways via the mTOR/PI3K/Akt cascade.[32-34]

Holland et al identified 100% VEGF expression in endometrial cancer tissue, with increased expression in areas of necrosis; only 20% expression in hyperplastic specimens; and no expression in benign specimens.[33] In uterine carcinoma, VEGF expression has been correlated with increased depth of invasion, lymphovascular space involvement, lymph node metastasis, and decreased survival.[35] Furthermore, hypoxia inducible factor 1α (HIF1α) has also been associated with more aggressive tumor characteristics.[36]

Clinical trials

Several phase II clinical trials have recently been published on the use of anti-angiogenesis agents in the treatment of advanced or recurrent endometrial cancer (see Table-PDF). Simpkins et al reported on bevacizumab with CT in patients with advanced or recurrent endometrial cancer. Five complete responses and six partial responses were seen, for an overall response rate of 73% (95% CI, 45%–91%). The median OS was 58 months (95% CI, 48–68 months).[36] The trial was closed early due to initiation of GOG protocol 86P evaluating CT and bevacizumab vs CT and temsirolimus vs ixabepilone, carboplatin, and bevacizumab (NCT00977574). GOG protocol 229E evaluated bevacizumab in 52 patients with advanced uterine carcinoma.[37] Seven patients (13.5%) experienced clinical responses, and 21 patients (40.4%) survived progression-free for at least 6 months. Median PFS and OS were 4.2 months and 10.5 months, respectively. Elevated VEGF in plasma was associated with lack of tumor response and increased mortality. GOG 229G enrolled 44 patients with recurrent or persistent disease to receive ziv-aflibercept (also called “VEGF Trap”), with a primary endpoint of PFS at 6 months, which was reached by 18 patients (41%). However, grade 3/4 adverse events were prohibitively high in this study, with 14 patients removed from the study because of toxicity.[38]

In GOG 229G, bevacizumab was also studied in combination with temsirolimus in patients with recurrent disease.[39] Twelve patients (24.5%) experienced clinical responses and 23 patients (46.9%) survived progression-free for at least 6 months. Median PFS and OS were 5.6 months and 16.9 months, respectively. Treatment toxicities were not insignificant: two cases each of gastrointestinal-vaginal fistula and intestinal perforation, and one case each of grade 3 epistaxis and grade 4 thrombosis/embolism. Three patient deaths were possibly treatment-related.

Bevacizumab has also been studied in conjunction with radiotherapy. In 2013, bevacizumab was used in the adjuvant setting in combination with chemoradiation, followed by adjuvant CT, in patients with high-risk endometrial carcinoma (grade 3 carcinoma with > 50% myometrial invasion, cervical stromal invasion, or known extrauterine extension confined to the pelvis).[40] Five of thirty patients developed recurrence, and eventually two died of disease. At the 1-year interim analysis, the investigators reported 100% OS, 90% PFS (95% CI, 72%–97%), 3.5% pelvic failure rate (95% CI, 0–10.2%), and 7% distant failure (95% CI, 0–16%), with largely well-tolerated adverse events. The first study to use bevacizumab alone with concurrent radiation was conducted in patients with recurrent endometrial or ovarian cancer with disease involving the vagina or lymph nodes (see Table-PDF).[41] In the 15 patients with recurrent endometrial cancer, the 1-year and 3-year PFS were 80% and 67%; 1-year and 3-year OS were 93% and 80%. Two patients with pelvic node involvement experienced no recurrence throughout the 65-month follow-up period. The findings support the use of concurrent bevacizumab and radiation as a tolerable and safe option in future trials.

Sorafenib was investigated in 56 patients with advanced uterine carcinoma and carcinosarcoma.[42] No patients with carcinosarcoma achieved an objective response. Two patients with uterine carcinoma (5%) had a partial response and 17 (42.5%) achieved stable disease. In patients with carcinoma, median OS was 11.4 months, while in patients with carcinosarcoma, median OS was 5 months. The authors concluded that sorafenib had minimal activity in this population.

Several multi-target TKIs have recently been evaluated in phase II trials (see Table-PDF). Sunitinib achieved an 18% response rate and a median OS of 19.4 months in 34 women with recurrent endometrial carcinoma or carcinosarcoma. Brivanib alaninate, a potent selective VEGFR/FGFR TKI, had less promising results, with a median OS of 10.7 months in GOG 229I. In GOG 229K, nintedanib lacked sufficient clinical efficacy to warrant further single-agent studies, but it may have a synergistic effect with paclitaxel in patients with specific p53 loss-of-function mutations.[43-45]

Ovarian Cancer

Affecting 22,240 women annually in the United States and leading to 14,030 deaths, ovarian cancer is the most lethal of the gynecologic malignancies.[29] The pathogenesis of ovarian cancer is a heterogeneous process, characterized by different types of tumors with widely different clinicopathologic features and metastatic patterns. There are several theories as to the origin of ovarian carcinoma. Serous ovarian cancer accounts for over 80% of cases, and current research suggests that these tumors originate from dysplastic cells from the fimbriated end of the fallopian tube.[47] Molecular studies have allowed classification of ovarian cancer into two categories[48]: Type I tumors (low-grade histologies) exhibit unique morphologic characteristics, have a clinically indolent course, and more commonly carry KRAS, BRAF, and ERBB2 mutations; while type II tumors (high-grade serous carcinomas, endometrioid carcinomas, undifferentiated carcinomas, and carcinosarcomas) have a different genetic fingerprint. Mutations in TP53 and CCNE1 (endcoding cyclin E1) amplification are more typical in high-grade serous carcinomas. Type II ovarian cancers are also distinguished by aneuploid genomes and a large burden of copy number gains and losses, making genomic instability a hallmark of ovarian cancer pathogenesis.[49]

At the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO), Gourley and colleagues further divided high-grade serous ovarian cancers into two clinically distinct molecular groups, the immune and proangiogenic subgroups.[50] The investigators’ translational research validated these subgroups on samples from the International Collaborative Ovarian Neoplasm (ICON)-7 trial and reported clinically significant differences in PFS and OS based on the molecular subgroup and receipt of bevacizumab. In the proangiogenic group, there was a nonsignificant trend toward improved median PFS with the addition of bevacizumab (17.4 months vs 12.3 months in controls). In the immune group, however, the addition of bevacizumab conferred a worse PFS (HR, 1.73; 95% CI, 1.12–2.68) and OS (HR, 2.00; 95% CI, 1.11–3.61) compared with chemotherapy alone. As our understanding of ovarian carcinogenesis becomes more nuanced, a subgroup of ovarian cancers will likely emerge for which anti-angiogenesis agents will have the largest impact on survival.

Bevacizumab and other anti-angiogenic therapies that target the VEGF pathway have demonstrated a survival advantage in seven clinical trials in ovarian cancer (see Table-PDF). Bevacizumab has been studied in multiple clinical settings: upfront adjuvant (GOG 218 and ICON-7), platinum-sensitive recurrent (OCEANS), and platinum-resistent recurrent (AURELIA).[10,51-57] Bevacizumab has now become the first FDA-approved anti-angiogenic therapy in ovarian cancer (approved for platinum-resistant recurrent disease). Pazopanib, a multi-target oral TKI of VEGFR, PDGFR, and stem cell factor receptor (c-KIT), has been evaluated as an adjuvant maintenance treatment for ovarian cancer, yielding an improvement in PFS (AGO-OVAR16 [Arbeitgemeinschaft Gynäkologische Onkologie Studiengruppe Ovarialkarzinom 16]). Cediranib has been evaluated in recurrent platinum-sensitive ovarian cancer and in BRCA mutation carriers in combination with the polymerase (ADP-ribose) polymerase (PARP) inhibitor olaparib, conferring an improvement in PFS of 7.7 months compared with olaparib alone. Nintedanib improved PFS when used in combination with CT in the primary adjuvant setting.[58]

Three additional phase III clinical trials utilizing bevacizumab in the treatment of ovarian cancer are currently awaiting publication. In GOG 262 (NCT01167712), a phase III trial exploring the addition of bevacizumab to standard CT or carboplatin with weekly, metronomic paclitaxel, the addition of bevacizumab appeared to lessen the PFS benefit of dose-dense paclitaxel. However, the trial did not randomize the use of bevacizumab, and this association may represent the results of an unplanned subset analysis. GOG 252 (NCT00951496), a phase III randomized three-arm trial for optimally cytoreduced patients, included bevacizumab (15 mg/kg) in all three arms while testing the efficacy of intraperitoneal carboplatin and weekly metronomic paclitaxel. The trial completed accrual in November 2011 and the data are maturing. GOG 213 (NCT00565851), a phase III randomized trial for patients with platinum-sensitive recurrence, included bevacizumab in the second-line and maintenance phases of treatment; the trial closed to accrual in August 2014. Interim data analysis was presented at the Society for Gynecologic Oncology (SGO) 2015 Annual Meeting, where it was reported that the addition of bevacizumab to chemotherapy in this platinum-sensitive population did improve PFS but without an OS benefit (the study’s primary endpoint).

Several multi-target TKIs are currently undergoing phase II investigation in patients with recurrent ovarian malignancy: imatinib (a PDGFR/c-KIT/Abl proto-oncogene TKI), sorafenib (a VEGFR/PDGFR/c-Raf TKI), and sunitinib (a VEGFR/PDGFR/KIT TKI), as well as others mentioned above. As results from these studies are forthcoming, many of the tested agents will likely be advanced to the phase III arena.

Cervical Cancer

Each year, 12,340 women are diagnosed with cervical cancer in the United States, and more than 4,000 will die from this disease.[1] The nature of cervical cancer oncogenesis makes this tumor type particularly susceptible to anti-angiogenic biologics. Starting with the preinvasive state, abnormal vascularity during colposcopic evaluation is a hallmark of more aggressive disease. Infection with human papillomavirus (HPV) and integration of viral DNA, specifically oncoproteins E6 and E7, into host cells causes malignant transformation via degradation/inactivation of tumor suppressors p53 and pRb. Eventually, this leads to HIF1α protein accumulation and increased VEGF expression, both of which facilitate the malignant transformation of HPV-infected cells.[58]

The first phase II clinical trial of bevacizumab alone in the treatment of recurrent cervical cancer (GOG 227C) enrolled a total of 46 patients and yielded a 35% response rate, a median OS of 7.3 months (95% CI, 6.1–10.4 months), and a median PFS of 3.4 months (95% CI, 2.5–4.5 months) (see Table-PDF).[59] The TKIs pazopanib and cediranib have also been studied in the phase II setting (see Table-PDF). VEG105281 randomly assigned 152 patients to pazopanib alone, lapatinib alone, or a combination of the two. The combination arm was discontinued due to toxicity; however, pazopanib alone improved both PFS (HR, 0.66; P = .013) and OS (HR, 0.67; P = .045), with a favorable toxicity profile (the only grade 3 adverse event seen in >10% of patients was diarrhea). Cediranib was evaluated in combination with CT in 69 women with advanced cervical cancer. The addition of cediranib improved median PFS by 5 weeks (8.8 vs 7.5 months; P = .046) and response rate by 24% (P = .03). Median OS was comparable in the two arms (14.8 vs 15.8 months; P = .41).

In 2009, GOG opened protocol 240, a four-arm phase III clinical trial exploring the effectiveness of anti-angiogenesis therapy and the effectiveness of non–platinum-based CT doublets in patients with recurrent, persistent, or metastatic cervical cancer.[60] The trial enrolled 452 patients, and bevacizumab was given in combination with cisplatin and paclitaxel, or paclitaxel and topotecan. The bevacizumab-containing arms demonstrated an improvement in OS of 17 vs 13.3 months (HR, 0.71; 95% CI, 0.54–0.95; P = .004; Figure 2). Significant improvements were also demonstrated in PFS (8.2 vs 5.9 months; HR, 0.67; 95% CI, 0.54–0.82; P = .0002) and response rate (48% vs 36%; P = .0008), without a significant deterioration in health-related quality of life. Noteworthy adverse events observed were largely limited to hypertension of grade 2 or higher (25% vs 2%), grade 3 or higher thromboembolic events (8% vs 1%), and grade 3 or higher gastrointestinal fistulas (3% vs 0) in the bevacizumab-containing arms and non–bevazcizumab-containing arms, respectively. In preliminary analyses, all 28 patients who developed fistulae in the trial had received prior radiation.[61] The impact of other factors associated with increased risk of fistula is under investigation. The improvement in OS seen in GOG 240 was the first for an anti-angiogenic agent in gynecologic cancer. The results of the trial led to a change in the standard of care for the treatment of patients with recurrent, persistent, or metastatic cervical cancer; within 6 months of publication, the use of bevacizumab in these settings was incorporated into the National Comprehensive Cancer Network treatment guidelines and was approved by the FDA for coverage under Medicare and Medicaid.


The reason bevacizumab resulted in an OS advantage in cervical cancer and not in ovarian cancer may lie in the biological differences between these two gynecologic cancers. Ovarian carcinogenesis is characterized by tumor heterogeneity stemming from genomic instability, nonequivalent gene expression, and copy number alterations. Conversely, the carcinogenic process in cervical malignancy is characterized by integration of viral DNA into host cells and has a predictable progression from the preinvasive state, which has made it particularly susceptible to screening interventions. Yet despite this possible homogeneity in pathogenesis, in the treatment setting, recurrent and persistent cervical cancer has historically demonstrated relative chemoresistance. Prior to GOG 240, eight phase III clinical trials investigated the use of cytotoxic CT in the recurrent or persistent setting, with limited response rates and survival (response rates ranged from 13% to 36%, median OS ranged from 6.5 to 12.9 months, and median PFS ranged 2.9 to 5.8 months).[62-66] The improvements in response rate and survival with the addition of bevacizumab to cytotoxic chemotherapy make an especially compelling argument for anti-angiogenic therapy in cervical cancer and highlight the role of angiogenesis in the carcinogenesis of this malignancy.

Another salient difference between epithelial ovarian cancer and cervical cancer with regard to clinical trial endpoints is the role of post-progression therapy. At the 2014 SGO Annual Meeting, Aghajanian and colleagues presented the final analysis of OS in the OCEANS trial that compared the addition of bevacizumab to the carboplatin/gemcitabine doublet vs carboplatin/gemcitabine plus placebo.[67] More than 88% of patients in the bevacizumab-containing arm and 90% of those in the placebo arm went on to receive anticancer therapy, with a median of 5 additional regimens. The chemosensitivity of ovarian cancer makes OS in late-phase clinical trials a controversial and potentially biased metric for multiple reasons. Both imbalanced treatment crossover after randomization and post-progressive therapies can dilute the effect of the study drug on OS. Detecting an OS advantage that derives from an improvement in PFS requires a short median post-progression interval (approximately 6 months),[68] a clinical scenario more often seen in advanced cervical carcinoma.


Anti-angiogenic therapies have a clear role in the treatment of gynecologic cancers. In 2014, the FDA approved the use of bevacizumab in advanced cervical cancer and platinum-resistant ovarian cancer, providing viable options for high-risk subgroups that previously had none. For most patients with gynecologic cancers, the response seen with anti-angiogenic therapy is unlikely to result in cure, and exploration of alternate therapies remains necessary. The discovery of new therapeutic agents and inevitably longer disease-free intervals will give rise to a new population of gynecologic cancer survivors, who will present novel challenges. Multimodal treatment strategies that include surgery, CT, radiotherapy, anti-angiogenesis therapy, and immunotherapy will allow patients with gynecologic malignancies to maximize their survival potential.

Financial Disclosure:Dr. Tewari has served in a limited capacity as a consultant and advisory board member for Roche-Genentech. Drs. Cripe and Liu have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30.

2. Growdon W, Foster R, Rueda B. Molecular targets in gynecologic cancers. In: del Carmen MG, Young RH, Schorge JO, Birrer MJ, editors. Uncommon gynecologic cancers; 1st ed. John Wiley & Sons;2015:6-12.

3. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9:239-52.

4. Witz IP. The tumor microenvironment: the making of a paradigm. Cancer Microenviron. 2009;2(suppl 1):9-17.

5. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-10.

6. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27-30.

7. Takahashi T, Yamaguchi S, Chida K, Shibuya M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001;20:2768-78.

8. Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3’-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998;273:30336-43.

9. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific growth factors and blood vessel formation. Nature. 2000;407:242-8.

10. Monk BJ, Poveda A, Vergote I, et al. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15:799-808.

11. Jain RK, Booth MF. What brings pericytes to tumor vessels? J Clin Invest. 2003;112:1134-6.

12. Rusnati M, Presta M. Fibroblast growth factors/fibroblast growth factor receptors as targets for the development of anti-angiogenesis strategies. Curr Pharm Des. 2007;13:2025-44.

13. Benjamin L, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998;1598:1591-8.

14. Farhadi M, Capelle H, Erber R. Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas. J Neurosurg. 2005;102:363-70.

15. Ferrara N, Gerber H-P, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-76.

16. Oda K, Matsuoka Y, Funahashi A, Kitano H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol Syst Biol. 2005;1:2005.0010.

17. Amin DN, Bielenberg DR, Lifshits E, et al. Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells. Microvasc Res. 2008;76:15-22.

18. Organ SL, Tsao M. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011(suppl 1):S7-S19.

19. Sawada K, Radjabi AR, Shinomiya N, et al. c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Res. 2007;67:1670-9.

20. Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol. 2013;5:212-7.

21. Benedito R, Rocha SF, Woeste M, et al. Notch-dependent VEGFR3 upregulation allows angiogenesis without VEGF-VEGFR2 signalling. Nature. 2012;484:110-4.

22. Jakobsson L, Bentley K, Gerhardt H. VEGFRs and Notch: a dynamic collaboration in vascular patterning. Biochem Soc Trans. 2009;37(Pt 6):1233-6.

23. Kim MP, Park SI, Kopetz S, Gallick GE. Src family kinases as mediators of endothelial permeability: effects on inflammation and metastasis. Cell Tissue Res. 2009;335:249-59.

24. Janku F, Wheler JJ, Naing A, et al. PIK3CA mutations in advanced cancers: characteristics and outcomes. Oncotarget. 2012;3:1566-75.

25. Pavlidou A, Vlahos NF. Molecular alterations of PI3K/Akt/mTOR pathway: a therapeutic target in endometrial cancer. Scien World J. 2014;2014:709736.

26. Jiang B-H, Liu L-Z. PI3K/PTEN signaling in tumorigenesis and angiogenesis. Biochim Biophys Acta. 2008;1784:150-8.

27. Wang S, Amato KR, Song W, et al. Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways. Mol Cell Biol. 12 Jan 2015. [Epub ahead of print]

28. Falcon BL, Barr S, Gokhale PC, et al. Reduced VEGF production, angiogenesis, and vascular regrowth contribute to the antitumor properties of dual mTORC1/mTORC2 inhibitors. Cancer Res. 2011;71:1573-83.

29. Rogers P, Abberton K, Susil B. Endothelial cell migratory signal produced by human endometrium during the menstrual cycle. Hum Reprod. 1992;7:1061-6.

30. Fujimoto J, Fujita H, Hosoda S, et al. Effect of medroxyprogesterone acetate on secondary spreading of endometrial cancer. Invasion Metastasis. 1989;9:209-15.

31. Tsuzuki T, Okada H, Cho H, et al. Divergent regulation of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor by hypoxia and female sex steroids in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2013;168:95-101.

32. Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005;65:10669-73.

33. Holland CM, Day K, Evans A, Smith SK. Expression of the VEGF and angiopoietin genes in endometrial atypical hyperplasia and endometrial cancer. Br J Cancer. 2003;89:891-8.

34. Feng Z, Gan H, Cai Z, et al. Aberrant expression of hypoxia-inducible factor 1α, TWIST and E-cadherin is associated with aggressive tumor phenotypes in endometrioid endometrial carcinoma. Jpn J Clin Oncol. 2013;43:396-403.

35. Hirai M, Nakagawara A, Oosaki T, et al. Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gynecol Oncol. 2001;80:181-8.

36. Simpkins F, Drake R, Escobar PF, et al. A phase II trial of paclitaxel, carboplatin, and bevacizumab in advanced and recurrent endometrial carcinoma (EMCA). Gynecol Oncol. 2015;136:240-5.

37. Aghajanian C, Sill MW, Darcy KM, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29:2259-65.

38. Coleman RL, Sill MW, Lankes HA, et al. A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 2012;127:538-43.

39. Alvarez EA, Brady WE, Walker JL, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129:22-7.

40. Viswanathan AN, Moughan J, Miller BE, et al. A phase 2 study of postoperative intensity modulated radiation therapy (IMRT) with concurrent cisplatin and bevacizumab (bev) followed by carboplatin and paclitaxel for patients with endometrial cancer: one-year results from RTOG 0921. Int J Radiat Oncol. 2013;87:S4–S5.

41. Viswanathan AN, Lee H, Berkowitz R, et al. A prospective feasibility study of radiation and concurrent bevacizumab for recurrent endometrial cancer. Gynecol Oncol. 2014;132:55-60.

42. Nimeiri HS, Oza AM, Morgan RJ, et al. A phase II study of sorafenib in advanced uterine carcinoma/carcinosarcoma: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 2010;117:37-40.

43. Castonguay V, Lheureux S, Welch S, et al. A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: a study of the Princess Margaret, Chicago and California Consortia. Gynecol Oncol. 2014;134:274-80.

44. Powell MA, Sill MW, Goodfellow PJ, et al. A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2014;135:38-43.

45. Dizon DS, Sill MW, Schilder JM, et al. A phase II evaluation of nintedanib (BIBF-1120) in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecol Oncol. 2014;135:441-5.

46. Erickson BK, Conner MG, Landen CN. The role of the fallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol. 2013;209:409-14.

47. Kurman RJ, Shih IM. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol. 2010;34:433-43.

48. Bowtell DDL. The genesis and evolution of high-grade serous ovarian cancer. Nat Rev Cancer. 2010;10:803-8.

49. Gourley C, McCavigan A, Perren T, et al. Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. J Clin Oncol. 2014;32(suppl):abstr 5502.

50. Burger RA. Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol. 2007;25:2902-8.

51. Perren T, Swart A. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-96.

52. Aghajanian C, Blank S V, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30:2039-45.

53. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32:1302-8.

54. Du Bois A, Floquet A, Kim JW, et al. Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer (AEOC): results of an international Intergroup trial (AGO-OVAR16). J Clin Oncol. 2013; 31(suppl):LBA5503.

55. Raja FA, Perren TJ, Embleton A, et al. Randomised double-blind phase iii trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: results of the ICON6 trial. Int J Gynecol Cancer. 2013;23(8 suppl 1):S7-S8.

56. Du Bois A, Kristensen G, Ray-Coquard I, et al. AGO-OVAR 12: a randomized placebo-controlled GCIG/ENGOT-intergroup phase III trial of standard frontline chemotherapy +/− nintedanib for advanced ovarian cancer. Int J Gynecol Cancer 2013;23(suppl 1):LBA1.

57. Hilberg F, Roth GJ, Krssak M, et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008;68:4774-82.

58. Choi KS, Bae MK, Jeong JW, et al. Hypoxia-induced angiogenesis during carcinogenesis. J Biochem Mol Biol. 2003;36:120-7.

59. Monk BJ, Sill MW, Burger RA, et al. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2009;27:1069-74.

60. Tewari KS, Sill MW, Long HJ, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734-43.

61. Willmott LJ, Java JJ, Monk BJ, et al. Fistulae in women treated with chemotherapy with and without bevacizumab for persistent, recurrent or metastatic cervical cancer in GOG-240. Intl Gynecol Cancer Soc 2014 Ann Meeting:abstr IGCSM-1194.

62. Omura GA, Blessing JA, Vaccarello L, et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997;15:165-71.

63. Bloss JD, Blessing JA, Behrens BC, et al. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2002;20:1832-7.

64. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22:3113-9.

65. Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23:4626-33.

66. Monk BJ, Sill MW, McMeekin DS, et al. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27:4649-55.

67. Aghajanian C, Goff BA, Nycum LR, et al. Independent radiologic review: bevacizumab in combination with gemcitabine and carboplatin in recurrent ovarian cancer. Gynecol Oncol. 2014;133:105-10.

68. Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst. 2009;101:1642-9.

69. Eskander RN, Tewari KS. Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma-mechanistics, review of phase IIi randomized clinical trials, and regulatory implications. Gynecol Oncol. 2014;132:496-505.

70. Liu JF, Barry WT, Birrer M, et al. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study. Lancet Oncol. 2014;15:1207-14. 71. Kudelka AP, Levy T, Verschraegen CF, et al. A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix. Clin Cancer Res. 1997;3:1501-5.

72. Monk BJ, Mas Lopez L, Zarba JJ, et al. Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer. J Clin Oncol. 2010;28:3562-9.

73. Symonds P, Gourley C, Davidson S, et al. CIRCCA: a randomized, double-blind phase II trial of carboplatin-paclitaxel plus cediranib versus carboplatin-paclitaxel plus placebo in metastatic/recurrent cervical cancer. Ann Oncol. 2014;25(suppl 5):abstr LBA25_PR.

74. Schefter T, Winter K, Kwon JS, et al; Radiation Therapy Oncology Group (RTOG). RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol. Biol Phys. 2014;88:101-5.