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Anti-angiogenesis agents in metastatic or recurrent cervical cancer
Gynecologic Oncology 116 (2010) 181–186
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
Review
Anti-angiogenesis agents in metastatic or recurrent cervical cancer Bradley J. Monk ⁎, Lyndsay J. Willmott, Daniele A. Sumner Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Building 56, 101 The City Drive, Orange CA 92868, USA
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Article history: Received 27 August 2009 Available online 27 October 2009 Keywords: Metastatic cervical cancer Angiogenesis Therapy
a b s t r a c t While the incidence of cervical cancer has declined significantly in the United States, it still remains a serious American health threat. When detected early, cervical cancer is generally curable. Early lesions are treated surgically, and locally advanced lesions are managed with concurrent cisplatin chemotherapy and pelvic radiation. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy. Current chemotherapeutic regimens are associated with significant side effects and only limited activity making the identification of active and tolerable novel targeted agents a high priority. Angiogenesis is central to cervical cancer development and progression. The dominant role of angiogenesis in cervical cancer seems to be directly related to HPV inhibition of p53 and stabilization of HIF-1 alpha, both of which increase VEGF. Bevacizumab binding and subsequent inactivation of VEGF seem to shrink cervical tumors and delay progression without appreciable toxicity, and are therefore being studied in a Gynecologic Oncology Group (GOG) phase III trial. Other intracellular tyrosine kinase inhibitors (TKIs) of angiogenesis such as pazopanib are also encouraging, especially in lieu of their oral administration. Further study of angiogenesis and its inhibition are ongoing. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiogenesis in cervical cancer and rationale for targeting . . . . . . . . . . . Bevacizumab, the first active targeted agent in recurrent cervical cancer . . . . . Are other molecular targets such as epidermal growth factor more attractive than Future directions and ongoing clinical trials . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Although likely an underestimation, Parkin and colleagues reported that cervical cancer affected 493,243 women worldwide in 2002, thereby making it the second most common female cancer. In addition, it is the third most common cause of female cancer mortality annually, with 273,505 deaths reported [1]. In developed countries such as the United States, cervical cancer incidence and mortality rates have declined approximately 75% over the past three decades. Still, the disease remains a serious American health threat with an
⁎ Corresponding author. Fax: +1 714 456 7754. E-mail address: [email protected] (B.J. Monk). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.09.033
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estimated incidence and mortality of 11,270 and 4,070 in 2009, respectively [2]. Cervical cancer is preventable and generally curable if detected early [3]. Treatment paradigms in the primary management of cervical cancer are well established, with early lesions being treated surgically and locally advanced lesions being managed with concurrent cisplatin chemotherapy and pelvic radiation [4,5]. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy usually consisting of a platinum-based doublet containing either paclitaxel or topotecan [6,7]. Future advances in treating metastatic or recurrent cervical carcinoma are unlikely unless novel systemic acting compounds can be identified and tested in prospective clinical trials. The most
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promising class of such agents targets the process of angiogenesis, which is central to cervical carcinogenesis and progression [8]. The current review outlines the rationale for studying anti-angiogenesis compounds in advanced and recurrent cervical cancer and reviews existing and emerging clinical data. Angiogenesis in cervical cancer and rationale for targeting Angiogenesis is the development of new blood vessels in areas of new tissue growth. This is a normal physiologic phenomenon associated with routine processes including wound healing and embryogenesis. It is also an important process that occurs almost universally in solid tumors as a response to the expansion of the cancer mass and its subsequent growth away from the existing blood supply. This causes the oxygen tension to fall beneath physiologic levels required for oxidative metabolism [9]. An important interplay of pro-angiogenic signaling occurs in response to the hypoxic state. A protein called hypoxia-inducible factor (HIF) 1 alpha is stabilized in these conditions and enters the nucleus where it forms a complex with another protein (HIF 1 beta). This complex is then able to act as a transcription factor allowing upregulation of growth factors including vascular endothelial growth factor (VEGF) [10,11]. The VEGF family includes six closely related molecules, but the most important angiogenic agent is VEGF-A. It was previously thought that the action of VEGF was mediated via a paracrine mechanism in which the VEGF produced by tumor cells stimulated endothelial cells that had numerous VEGF receptors [9]. The current view is that VEGF action is actually mediated in several ways. VEGF originates from many cell types including tumor-associated stromal cells. There is also the theory that tumor cells of many types may actually produce VEGF that then acts in an autocrine fashion to stimulate VEGF receptors located on their own cell surface. One of the dominant functions of VEGF is endothelial cell proliferation and migration toward tumor cells. As this occurs, there is extensive endothelial membrane remodeling leading to neovascularization. The maturation of these new blood vessels is accomplished via the recruitment of pericytes, which stabilize the nascent capillaries. Interestingly, once maturation of the new vasculature has occurred, growth factors are no longer required for the survival of the endothelium. In neoplastic growth, however, maturation of the vasculature is usually incomplete. This is secondary to the constant vascular remodeling into the tissue stroma, which enables tumor growth and invasion. Thus, the endothelial cells of these immature blood vessels require growth signals for survival to avoid apoptosis [12]. Sprouting-type angiogenesis, as described above, is an important mechanism in cervical cancer neovascularization. However, before angiogenesis occurs in the cervix, tumor promotion occurs by persistent local infection with one of the cancer causing human papillomavirus (HPV) types. Ongoing HPV infection, usually associated with genomic HPV integration, leads to severe dysregulation of p53, a tumor suppressor gene. The dysregulation of p53 is mediated by the oncogenic protein HPV E6 via two mechanisms. The first involves blockage of induction of p53 following DNA damage, which normally allows the cell to enter cell cycle arrest and undergo DNA repair, or if fatally injured, triggers the cell to undergo apoptosis. The second pathway involves E6 induced ubiquitination of p53 and subsequent degradation of the protein (Fig. 1). The down-regulation of the tumor suppressor gene p53 has many important consequences, including increasing angiogenic potential through the up-regulation of VEGF [8]. In addition to interfering with p53 function, HPV E6 has also been shown to independently enhance induction of HIF-1 alpha in experimental models, thus increasing VEGF through a second mechanism. This finding sheds even more light on the mechanism by which HPV contributes to angiogenesis in cervical lesions [13].
Fig. 1. HPV E6 is a viral oncogenic protein that interferes with p53, a tumor suppressor protein, via two mechanisms. The first is the blockage of p53 induction following DNA damage, which would usually allow for either cell cycle arrest and DNA repair or apoptosis. The second is mediated by binding of HPV E6 to p53, which leads to ubiquitination of p53 and its subsequent degradation. With either blockage of p53 induction or increased p53 degradation, a series of pro-angiogenic pathways are triggered. This includes the up-regulation of VEGF and subsequently angiogenesis (adopted from Willmott and Monk [8]).
Previous studies in cervical cancer have assessed angiogenesis as an independent risk factor for the disease. One study evaluated formalin-fixed paraffin-embedded tumor biopsies in 111 patients treated with pelvic irradiation for distance to the closest microvessel and intratumoral microvessel density (MVD). Patients whose cancers demonstrated high vascularity had a 50% 5-year survival, while those whose cancers exhibited low vascularity had a 65% 5-year survival. On multivariate analysis, MVD was a significant prognostic marker, as high tumor vascularity was associated with lower overall survival and locoregional control [14]. Almost a decade later, a prospective analysis of various angiogenesis markers utilizing immunohistochemistry was performed on cervical tumor specimens from a multicenter randomized phase III trial (Southwest Oncology Group 8797/GOG 109/Radiation Therapy Oncology Group 91-12). This study investigated the significance of adding cisplatin-based chemotherapy to adjuvant radiation following radical hysterectomy when high risk factors such as nodal metastases were present. In contrast to the prior study, the investigators showed that increased tumor angiogenesis as measured by CD31-MVD (a nonspecific endothelial marker) was an independent prognostic marker for improved progression-free and overall survival. The authors hypothesized that this finding might be explained by improved treatment response, potentially mediated by better chemotherapeutic delivery or enhanced radiation therapy, in well-vascularized, welloxygenated tumors [15]. This concept was further supported by another analysis of the same tumor samples looking at CA-IX, one of the most promising endogenous markers of cellular hypoxia. CA-IX expression is controlled by the transcription factor HIF-1 alpha and is up-regulated in hypoxic regions of tumor tissues. Although this study did not show a correlation between CA-IX expression and several angiogenesis biomarkers including CD31-MVD, CD105-MVD, thrombospondin-1 (TSP-1), VEGF-A, or p53, an interesting association was observed between CD31-MVD, CA-IX expression and prognosis. Women who had tumors with high CD31-MVD (marker for angiogenesis) and low CA-IX (marker for hypoxia) had the best progression-free survival (PFS) and overall survival (OS), whereas those with low CD31-MVD and low CA-IX had intermediate PFS and OS and those with low CD31-MVD and high CA-IX had the worst PFS and OS (Fig. 2). Adjusted Cox regression modeling demonstrated that CA-IX and CD31-MVD were each independent prognostic factors for PFS and OS. Taken together, these findings support the hypothesis that improved treatment response is observed in the wellvascularized and well-oxygenated cervical cancers with high CD31MVD and low CA-IX expression [16].
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Fig. 2. Immunohistochemical analysis of cervical cancers after radical hysterectomy from a multicenter randomized phase III trial (Southwest Oncology Group 8797/GOG 109/ Radiation Therapy Oncology Group 91-12) investigating the addition of cisplatin-based chemotherapy to adjuvant radiation. CA-IX is controlled by HIF-1 and is up-regulated in hypoxic of tumors. CD31 is an endothelial marker of angiogenesis. Vascular and well-oxygenated tumors were associated with the best survival (adopted from Liao et al. [16]).
Radiologic techniques have been extensively studied as a noninvasive modality to assess angiogenesis in cervical tumors. For example, MRI imaging sequence with compartmental analysis has proven helpful to measure the in vivo blood flow in cervical cancers [12]. This technique can allow quantification of volumetric and vascular characteristics of tumors. In addition, contrast enhanced dynamic MRI (CD-MRI) may be helpful to measure tumor cellular volume, vessel permeability, and vascular volume. One study examined CD-MRI-derived characteristics and histologic microvessel density counts in patients with primary or recurrent uterine cervical cancer. Two pharmacokinetic parameters—amplitude and exchange rate constant—were calculated from a CD-MRI series in these patients. Both of these parameters increased with increasing histologic microvessel density counts. The technique was also tested in primary cervical cancer treated by radical hysterectomy, where the exchange rate constant was found to be a significant predictor of patient survival [17]. Markers of tumor angiogenesis can also be evaluated in cervical cancer patients through serologic testing. For example, mediators of neovascularization including VEGF and angiogenin (a potent mediator of neovascularization secreted by both inflammatory and malignant cells) have been shown to correlate with stage of disease and prognosis [18–21]. Clearly, there is more to learn about angiogenesis related to cervical cancer progression and prognosis, but one point is irrefutable, angiogenesis is pivotal in this disease and a rational target for therapy.
persistent or recurrent cancer, but these studies only investigate targeted agents [23]. GOG protocol 227C was a phase II multicenter trial evaluating single agent bevacizumab therapy among 46 women with persistent or recurrent squamous cell carcinoma of the cervix [24]. Bevacizumab is a humanized monoclonal antibody directed against VEGF-A and was the first clinically available anti-angiogenic agent in the United States [25]. It has been successfully studied in many solid tumors including colon, lung, breast, kidney, brain, and ovarian cancer. In GOG protocol 227C, the PFS probability greater than 6 months was 0.24 (two-sided 90% CI, 14% to 37%) with median OS of 7.29 months (95% CI, 6.11 to 10.41 months), and a response rate of 10.9 percent (two-sided exact binomial 90% CI, 4.4% to 21.5%). The overall median PFS was 3.40 months (95% CI, 2.53 to 4.53 months), and the median response duration was 6.21 months (range, 2.83 to 8.28 months). The single agent bevacizumab regimen compared favorably with prior regimens that evaluated this particular patient population (Fig. 3). This study demonstrated several Grade 3/4 adverse events that were
Bevacizumab, the first active targeted agent in recurrent cervical cancer For over three decades, the Gynecologic Oncology Group (GOG) has performed phase II and III studies among women suffering from advanced and recurrent cervical cancer [22]. The phase II program consists of three series of protocols or “queues”. The 76 protocol series investigates compounds in the setting of stage IVB-untreated disease or after failing primary therapy including combination chemotherapy with radiation. The 127 GOG protocol series allows one prior systemic chemotherapeutic regimen for management of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer is not counted as a systemic chemotherapy regimen. Finally, the 227 series allows up to two prior cytotoxic therapies for
Fig. 3. Results of Gynecologic Oncology Group (GOG) protocol 227-C: phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix. Progression-free survival (PFS) from GOG 227-C (blue) is compared to the PFS from studies in the GOG historical database (failing one or two cytotoxic regimens, not including chemoradiotherapy [RT]) (adopted from Monk et al. [24]).
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at least possibly related to bevacizumab therapy, including hypertension (N = 7), thromboembolism (N = 5), gastrointestinal complaints (N = 4), anemia (N = 2), vaginal bleeding (N = 1), neutropenia (N = 1), and fistula (N = 1). One Grade 5 infection was observed. The results of 227-C are not surprising given what is known about angiogenesis in cervical cancer. Importantly, no unusual toxicities were identified in GOG 227-C, suggesting that bevacizumab is not only active in treating recurrent cervical cancer but also safe. Are other molecular targets such as epidermal growth factor more attractive than angiogenesis in advanced or recurrent cervical cancer? Other growth factors have been targets of interest in treating advanced and recurrent cervical cancer. One of these is the epidermal growth factor (EGF) family of tyrosine kinases, of which EGF type 1 (EGFR) is a member [23]. The proteins in this family possess an extracellular ligand binding domain, a single hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase-containing domain. When endogenous ligand binding occurs at the extracellular domain, EGFR forms receptor homodimer or heterodimers and activates the intrinsic tyrosine kinase-containing domain. After this occurs, a network of signal transduction pathways is induced, including promotion of proliferation, motility, invasion, and angiogenesis. EGFR is overexpressed in a number of solid tumors, including nonsmall cell lung cancer, colorectal cancer, and head and neck cancer. In cases of squamous cell carcinoma of the cervix, EGFR has been found to be overexpressed in up to 85% of cases, and expression has been associated with poor prognosis and higher stage [26]. Cetuximab is a chimeric immunoglobulin G2 monoclonal antibody derived from the mouse monoclonal antibody 225. Preclinical models in cervical cancer have demonstrated sensitivity to cetuximabmediated cellular cytotoxicity and inhibition of tumor growth [27]. There are several ongoing trials of cetuximab in treatment of cervical cancer, including a study evaluating the efficacy of cetuximab monotherapy in persistent or recurrent carcinoma of the cervix (GOG 277E) [28] and the addition of cetuximab to radiotherapy for treatment of early carcinoma of the cervix (GOG 9918) [29]. Unfortunately, the two recently completed GOG studies investigating EGF-based therapy have both been negative. When added to IV cisplatin in treating persistent or recurrent carcinoma of the cervix (GOG 76DD), cetuximab increased toxicity compared to historical controls using cisplatin alone and only had a response rate of 11.6% [30]. Erlotinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) and was
also inactive when studied in GOG 227D [31]. There were no objective responses, and only a single subject (4%) remained progression-free for greater than 6 months. Both of these studies are disappointing given the strong rationale for studying EGF-based therapy in cervical cancer. A recently reported head-to-head randomized phase II trial compared EGF-based therapy to anti-angiogenesis therapy in women with advanced or recurrent cervical cancer (Fig. 4). This study evaluated lapatinib, an oral EGFR-TKI with HER2 activity, versus another oral tyrosine kinase inhibitor, pazopanib, which targets VEGFR, platelet-derived growth factor receptor (PDGFR), and c-Kit. This study convincingly suggested the superiority of anti-angiogenesis therapy. Pazopanib improved PFS (hazard ratio [HR], 0.66; 90% CI, 0.48–0.91; P = 0.013) and OS (HR, 0.67; 90% CI, 0.46–0.99; P = 0.045). The only grade 3 adverse event that occurred in greater than 10% of subjects was diarrhea (11% pazopanib and 13% lapatinib). Pazopanib offers great promise in treating cervical cancer because of its oral administration and the low incidence of serious toxicity. This is especially important because the majority of cervical cancer cases occur in the developing world and therapy for advanced and recurrent disease is heavily focused on palliation, which renders treatmentrelated severe side effects unacceptable. All reports of anti-angiogenesis agents in advanced and recurrent cervical cancer have not been as encouraging as the bevacizumab and pazopanib trials. The NCIC Canada Clinical Trials Group recently reported on a single-agent study of sunitinib malate, an oral, multitargeted TKI that inhibits VEGFR, c-Kit, and PDGFR among 19 patients with locally advanced or metastatic cervical carcinoma. Although 84% of those enrolled had stable disease (median duration, 4.4 months, 2.3–17 months), there were no objective responses and the median time to progression was 3.5 months (range, 2.7–7.0 months). Four patients developed fistulae on study treatment, and an additional patient developed a fistula 3.5 months after discontinuation of therapy. All five patients had received either prior chemoradiation or pelvic radiation alone [33]. This is quite concerning since gastrointestinal (GI) “perforation” is a known complication of this class of agents, but it is noteworthy that there was only one GI fistula in GOG 227C. Future directions and ongoing clinical trials Based on the success of bevacizumab in GOG 227C, a cohort of heavily pretreated patients, it seems logical to study this exciting new agent in conjunction with other first line therapies in stage IVB or
Fig. 4. Study design of VEG105281. Inclusion criteria included women with FIGO stage IVB, recurrent or persistent cervical cancer having received zero or one prior chemotherapy regimen for advanced/recurrent disease. Pazopanib (Paz) and lapatinib (Lap) are oral tyrosine kinase inhibitors that target VEGFR, PDGFR, and c-Kit, or EGFR and HER2, respectively. The primary endpoint was progression-free survival (PFS), and this study demonstrated the superiority of anti-angiogenesis therapy (Paz) compared to ant-EGF/HER2 (Lap) intervention. Secondary endpoints, response rate (ORR), and survival (OS) supported this conclusion (adopted from Monk et al. [32]).
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Fig. 5. Schema for Gynecologic Oncology Group protocol 240, a trial designed to evaluate four regimens against cervical cancer in a head-to-head fashion. This includes paclitaxel plus cisplatin, topotecan plus cisplatin, and both regimens with bevacizumab [33].
recurrent/persistent cervical carcinoma. However, the cost of bevacizumab and the limited availability of this agent in the developing world where cervical cancer is a common source of morbidity and mortality are a serious concern and deserve careful consideration. In addition, the cost-effectiveness of agents such as bevacizumab where only small increases in RR, PFS, and OS are realized requires future study although cheaper or generic alternatives may be available in the near future. GOG 240 is a study that involves randomization to one of four regimens: paclitaxel/cisplatin, paclitaxel/cisplatin plus bevacizumab, paclitaxel/topotecan, and paclitaxel/topotecan plus bevacizumab (Fig. 5) [34]. This study will evaluate OS from date of randomization and frequency and severity of adverse events as its primary endpoints. Secondary endpoints include PFS from date of randomization and frequency of objective tumor response. Because of the limited safety profile of these combinations, a carefully monitored safety plan is in place as well as an early assessment of toxicity. In addition to this phase III trial, other anti-angiogenesis compounds that target proangiogenesis factors other than VEGFR will soon be investigated by the GOG in the 227 protocol series. For example, brivanib, a highly potent dual inhibitor of VEGFR and fibroblast growth factor receptor (FGFR) and a member of a new class of pyrrolo[2,1-f]-1,2,4]triazinebased selective VEGFR-2 inhibitors, will soon be under study. Conclusion Angiogenesis is central to cervical cancer development and progression. The dominant role of angiogenesis in cervical cancer seems to be directly related to HPV inhibition of p53 and stabilization of HIF-1 alpha, both of which increase VEGF. The binding and inactivation of VEGF by bevacizumab seem to shrink cervical tumors
and delay progression without appreciable toxicity and are being studied in a GOG phase III trial. Other intracellular TKIs of angiogenesis such as pazopanib are also encouraging especially in lieu of their oral administration. Further study of angiogenesis and its inhibition is ongoing and represents one of the highest priorities in therapeutic gynecologic oncology today.
Conflict of interest statement There are no financial relationships and/or conflicts of interest between Dr. Willmott and Ms Sumner and the companies whose products are the subject of this article. Dr. Monk has received research funding from GlaxoSmithKline the maker of pazopanib.
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Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o
Review
Anti-angiogenesis agents in metastatic or recurrent cervical cancer Bradley J. Monk ⁎, Lyndsay J. Willmott, Daniele A. Sumner Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Building 56, 101 The City Drive, Orange CA 92868, USA
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Article history: Received 27 August 2009 Available online 27 October 2009 Keywords: Metastatic cervical cancer Angiogenesis Therapy
a b s t r a c t While the incidence of cervical cancer has declined significantly in the United States, it still remains a serious American health threat. When detected early, cervical cancer is generally curable. Early lesions are treated surgically, and locally advanced lesions are managed with concurrent cisplatin chemotherapy and pelvic radiation. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy. Current chemotherapeutic regimens are associated with significant side effects and only limited activity making the identification of active and tolerable novel targeted agents a high priority. Angiogenesis is central to cervical cancer development and progression. The dominant role of angiogenesis in cervical cancer seems to be directly related to HPV inhibition of p53 and stabilization of HIF-1 alpha, both of which increase VEGF. Bevacizumab binding and subsequent inactivation of VEGF seem to shrink cervical tumors and delay progression without appreciable toxicity, and are therefore being studied in a Gynecologic Oncology Group (GOG) phase III trial. Other intracellular tyrosine kinase inhibitors (TKIs) of angiogenesis such as pazopanib are also encouraging, especially in lieu of their oral administration. Further study of angiogenesis and its inhibition are ongoing. © 2009 Elsevier Inc. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiogenesis in cervical cancer and rationale for targeting . . . . . . . . . . . Bevacizumab, the first active targeted agent in recurrent cervical cancer . . . . . Are other molecular targets such as epidermal growth factor more attractive than Future directions and ongoing clinical trials . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Although likely an underestimation, Parkin and colleagues reported that cervical cancer affected 493,243 women worldwide in 2002, thereby making it the second most common female cancer. In addition, it is the third most common cause of female cancer mortality annually, with 273,505 deaths reported [1]. In developed countries such as the United States, cervical cancer incidence and mortality rates have declined approximately 75% over the past three decades. Still, the disease remains a serious American health threat with an
⁎ Corresponding author. Fax: +1 714 456 7754. E-mail address: [email protected] (B.J. Monk). 0090-8258/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2009.09.033
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estimated incidence and mortality of 11,270 and 4,070 in 2009, respectively [2]. Cervical cancer is preventable and generally curable if detected early [3]. Treatment paradigms in the primary management of cervical cancer are well established, with early lesions being treated surgically and locally advanced lesions being managed with concurrent cisplatin chemotherapy and pelvic radiation [4,5]. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy usually consisting of a platinum-based doublet containing either paclitaxel or topotecan [6,7]. Future advances in treating metastatic or recurrent cervical carcinoma are unlikely unless novel systemic acting compounds can be identified and tested in prospective clinical trials. The most
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promising class of such agents targets the process of angiogenesis, which is central to cervical carcinogenesis and progression [8]. The current review outlines the rationale for studying anti-angiogenesis compounds in advanced and recurrent cervical cancer and reviews existing and emerging clinical data. Angiogenesis in cervical cancer and rationale for targeting Angiogenesis is the development of new blood vessels in areas of new tissue growth. This is a normal physiologic phenomenon associated with routine processes including wound healing and embryogenesis. It is also an important process that occurs almost universally in solid tumors as a response to the expansion of the cancer mass and its subsequent growth away from the existing blood supply. This causes the oxygen tension to fall beneath physiologic levels required for oxidative metabolism [9]. An important interplay of pro-angiogenic signaling occurs in response to the hypoxic state. A protein called hypoxia-inducible factor (HIF) 1 alpha is stabilized in these conditions and enters the nucleus where it forms a complex with another protein (HIF 1 beta). This complex is then able to act as a transcription factor allowing upregulation of growth factors including vascular endothelial growth factor (VEGF) [10,11]. The VEGF family includes six closely related molecules, but the most important angiogenic agent is VEGF-A. It was previously thought that the action of VEGF was mediated via a paracrine mechanism in which the VEGF produced by tumor cells stimulated endothelial cells that had numerous VEGF receptors [9]. The current view is that VEGF action is actually mediated in several ways. VEGF originates from many cell types including tumor-associated stromal cells. There is also the theory that tumor cells of many types may actually produce VEGF that then acts in an autocrine fashion to stimulate VEGF receptors located on their own cell surface. One of the dominant functions of VEGF is endothelial cell proliferation and migration toward tumor cells. As this occurs, there is extensive endothelial membrane remodeling leading to neovascularization. The maturation of these new blood vessels is accomplished via the recruitment of pericytes, which stabilize the nascent capillaries. Interestingly, once maturation of the new vasculature has occurred, growth factors are no longer required for the survival of the endothelium. In neoplastic growth, however, maturation of the vasculature is usually incomplete. This is secondary to the constant vascular remodeling into the tissue stroma, which enables tumor growth and invasion. Thus, the endothelial cells of these immature blood vessels require growth signals for survival to avoid apoptosis [12]. Sprouting-type angiogenesis, as described above, is an important mechanism in cervical cancer neovascularization. However, before angiogenesis occurs in the cervix, tumor promotion occurs by persistent local infection with one of the cancer causing human papillomavirus (HPV) types. Ongoing HPV infection, usually associated with genomic HPV integration, leads to severe dysregulation of p53, a tumor suppressor gene. The dysregulation of p53 is mediated by the oncogenic protein HPV E6 via two mechanisms. The first involves blockage of induction of p53 following DNA damage, which normally allows the cell to enter cell cycle arrest and undergo DNA repair, or if fatally injured, triggers the cell to undergo apoptosis. The second pathway involves E6 induced ubiquitination of p53 and subsequent degradation of the protein (Fig. 1). The down-regulation of the tumor suppressor gene p53 has many important consequences, including increasing angiogenic potential through the up-regulation of VEGF [8]. In addition to interfering with p53 function, HPV E6 has also been shown to independently enhance induction of HIF-1 alpha in experimental models, thus increasing VEGF through a second mechanism. This finding sheds even more light on the mechanism by which HPV contributes to angiogenesis in cervical lesions [13].
Fig. 1. HPV E6 is a viral oncogenic protein that interferes with p53, a tumor suppressor protein, via two mechanisms. The first is the blockage of p53 induction following DNA damage, which would usually allow for either cell cycle arrest and DNA repair or apoptosis. The second is mediated by binding of HPV E6 to p53, which leads to ubiquitination of p53 and its subsequent degradation. With either blockage of p53 induction or increased p53 degradation, a series of pro-angiogenic pathways are triggered. This includes the up-regulation of VEGF and subsequently angiogenesis (adopted from Willmott and Monk [8]).
Previous studies in cervical cancer have assessed angiogenesis as an independent risk factor for the disease. One study evaluated formalin-fixed paraffin-embedded tumor biopsies in 111 patients treated with pelvic irradiation for distance to the closest microvessel and intratumoral microvessel density (MVD). Patients whose cancers demonstrated high vascularity had a 50% 5-year survival, while those whose cancers exhibited low vascularity had a 65% 5-year survival. On multivariate analysis, MVD was a significant prognostic marker, as high tumor vascularity was associated with lower overall survival and locoregional control [14]. Almost a decade later, a prospective analysis of various angiogenesis markers utilizing immunohistochemistry was performed on cervical tumor specimens from a multicenter randomized phase III trial (Southwest Oncology Group 8797/GOG 109/Radiation Therapy Oncology Group 91-12). This study investigated the significance of adding cisplatin-based chemotherapy to adjuvant radiation following radical hysterectomy when high risk factors such as nodal metastases were present. In contrast to the prior study, the investigators showed that increased tumor angiogenesis as measured by CD31-MVD (a nonspecific endothelial marker) was an independent prognostic marker for improved progression-free and overall survival. The authors hypothesized that this finding might be explained by improved treatment response, potentially mediated by better chemotherapeutic delivery or enhanced radiation therapy, in well-vascularized, welloxygenated tumors [15]. This concept was further supported by another analysis of the same tumor samples looking at CA-IX, one of the most promising endogenous markers of cellular hypoxia. CA-IX expression is controlled by the transcription factor HIF-1 alpha and is up-regulated in hypoxic regions of tumor tissues. Although this study did not show a correlation between CA-IX expression and several angiogenesis biomarkers including CD31-MVD, CD105-MVD, thrombospondin-1 (TSP-1), VEGF-A, or p53, an interesting association was observed between CD31-MVD, CA-IX expression and prognosis. Women who had tumors with high CD31-MVD (marker for angiogenesis) and low CA-IX (marker for hypoxia) had the best progression-free survival (PFS) and overall survival (OS), whereas those with low CD31-MVD and low CA-IX had intermediate PFS and OS and those with low CD31-MVD and high CA-IX had the worst PFS and OS (Fig. 2). Adjusted Cox regression modeling demonstrated that CA-IX and CD31-MVD were each independent prognostic factors for PFS and OS. Taken together, these findings support the hypothesis that improved treatment response is observed in the wellvascularized and well-oxygenated cervical cancers with high CD31MVD and low CA-IX expression [16].
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Fig. 2. Immunohistochemical analysis of cervical cancers after radical hysterectomy from a multicenter randomized phase III trial (Southwest Oncology Group 8797/GOG 109/ Radiation Therapy Oncology Group 91-12) investigating the addition of cisplatin-based chemotherapy to adjuvant radiation. CA-IX is controlled by HIF-1 and is up-regulated in hypoxic of tumors. CD31 is an endothelial marker of angiogenesis. Vascular and well-oxygenated tumors were associated with the best survival (adopted from Liao et al. [16]).
Radiologic techniques have been extensively studied as a noninvasive modality to assess angiogenesis in cervical tumors. For example, MRI imaging sequence with compartmental analysis has proven helpful to measure the in vivo blood flow in cervical cancers [12]. This technique can allow quantification of volumetric and vascular characteristics of tumors. In addition, contrast enhanced dynamic MRI (CD-MRI) may be helpful to measure tumor cellular volume, vessel permeability, and vascular volume. One study examined CD-MRI-derived characteristics and histologic microvessel density counts in patients with primary or recurrent uterine cervical cancer. Two pharmacokinetic parameters—amplitude and exchange rate constant—were calculated from a CD-MRI series in these patients. Both of these parameters increased with increasing histologic microvessel density counts. The technique was also tested in primary cervical cancer treated by radical hysterectomy, where the exchange rate constant was found to be a significant predictor of patient survival [17]. Markers of tumor angiogenesis can also be evaluated in cervical cancer patients through serologic testing. For example, mediators of neovascularization including VEGF and angiogenin (a potent mediator of neovascularization secreted by both inflammatory and malignant cells) have been shown to correlate with stage of disease and prognosis [18–21]. Clearly, there is more to learn about angiogenesis related to cervical cancer progression and prognosis, but one point is irrefutable, angiogenesis is pivotal in this disease and a rational target for therapy.
persistent or recurrent cancer, but these studies only investigate targeted agents [23]. GOG protocol 227C was a phase II multicenter trial evaluating single agent bevacizumab therapy among 46 women with persistent or recurrent squamous cell carcinoma of the cervix [24]. Bevacizumab is a humanized monoclonal antibody directed against VEGF-A and was the first clinically available anti-angiogenic agent in the United States [25]. It has been successfully studied in many solid tumors including colon, lung, breast, kidney, brain, and ovarian cancer. In GOG protocol 227C, the PFS probability greater than 6 months was 0.24 (two-sided 90% CI, 14% to 37%) with median OS of 7.29 months (95% CI, 6.11 to 10.41 months), and a response rate of 10.9 percent (two-sided exact binomial 90% CI, 4.4% to 21.5%). The overall median PFS was 3.40 months (95% CI, 2.53 to 4.53 months), and the median response duration was 6.21 months (range, 2.83 to 8.28 months). The single agent bevacizumab regimen compared favorably with prior regimens that evaluated this particular patient population (Fig. 3). This study demonstrated several Grade 3/4 adverse events that were
Bevacizumab, the first active targeted agent in recurrent cervical cancer For over three decades, the Gynecologic Oncology Group (GOG) has performed phase II and III studies among women suffering from advanced and recurrent cervical cancer [22]. The phase II program consists of three series of protocols or “queues”. The 76 protocol series investigates compounds in the setting of stage IVB-untreated disease or after failing primary therapy including combination chemotherapy with radiation. The 127 GOG protocol series allows one prior systemic chemotherapeutic regimen for management of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix. Chemotherapy administered in conjunction with primary radiation as a radio-sensitizer is not counted as a systemic chemotherapy regimen. Finally, the 227 series allows up to two prior cytotoxic therapies for
Fig. 3. Results of Gynecologic Oncology Group (GOG) protocol 227-C: phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix. Progression-free survival (PFS) from GOG 227-C (blue) is compared to the PFS from studies in the GOG historical database (failing one or two cytotoxic regimens, not including chemoradiotherapy [RT]) (adopted from Monk et al. [24]).
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at least possibly related to bevacizumab therapy, including hypertension (N = 7), thromboembolism (N = 5), gastrointestinal complaints (N = 4), anemia (N = 2), vaginal bleeding (N = 1), neutropenia (N = 1), and fistula (N = 1). One Grade 5 infection was observed. The results of 227-C are not surprising given what is known about angiogenesis in cervical cancer. Importantly, no unusual toxicities were identified in GOG 227-C, suggesting that bevacizumab is not only active in treating recurrent cervical cancer but also safe. Are other molecular targets such as epidermal growth factor more attractive than angiogenesis in advanced or recurrent cervical cancer? Other growth factors have been targets of interest in treating advanced and recurrent cervical cancer. One of these is the epidermal growth factor (EGF) family of tyrosine kinases, of which EGF type 1 (EGFR) is a member [23]. The proteins in this family possess an extracellular ligand binding domain, a single hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase-containing domain. When endogenous ligand binding occurs at the extracellular domain, EGFR forms receptor homodimer or heterodimers and activates the intrinsic tyrosine kinase-containing domain. After this occurs, a network of signal transduction pathways is induced, including promotion of proliferation, motility, invasion, and angiogenesis. EGFR is overexpressed in a number of solid tumors, including nonsmall cell lung cancer, colorectal cancer, and head and neck cancer. In cases of squamous cell carcinoma of the cervix, EGFR has been found to be overexpressed in up to 85% of cases, and expression has been associated with poor prognosis and higher stage [26]. Cetuximab is a chimeric immunoglobulin G2 monoclonal antibody derived from the mouse monoclonal antibody 225. Preclinical models in cervical cancer have demonstrated sensitivity to cetuximabmediated cellular cytotoxicity and inhibition of tumor growth [27]. There are several ongoing trials of cetuximab in treatment of cervical cancer, including a study evaluating the efficacy of cetuximab monotherapy in persistent or recurrent carcinoma of the cervix (GOG 277E) [28] and the addition of cetuximab to radiotherapy for treatment of early carcinoma of the cervix (GOG 9918) [29]. Unfortunately, the two recently completed GOG studies investigating EGF-based therapy have both been negative. When added to IV cisplatin in treating persistent or recurrent carcinoma of the cervix (GOG 76DD), cetuximab increased toxicity compared to historical controls using cisplatin alone and only had a response rate of 11.6% [30]. Erlotinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) and was
also inactive when studied in GOG 227D [31]. There were no objective responses, and only a single subject (4%) remained progression-free for greater than 6 months. Both of these studies are disappointing given the strong rationale for studying EGF-based therapy in cervical cancer. A recently reported head-to-head randomized phase II trial compared EGF-based therapy to anti-angiogenesis therapy in women with advanced or recurrent cervical cancer (Fig. 4). This study evaluated lapatinib, an oral EGFR-TKI with HER2 activity, versus another oral tyrosine kinase inhibitor, pazopanib, which targets VEGFR, platelet-derived growth factor receptor (PDGFR), and c-Kit. This study convincingly suggested the superiority of anti-angiogenesis therapy. Pazopanib improved PFS (hazard ratio [HR], 0.66; 90% CI, 0.48–0.91; P = 0.013) and OS (HR, 0.67; 90% CI, 0.46–0.99; P = 0.045). The only grade 3 adverse event that occurred in greater than 10% of subjects was diarrhea (11% pazopanib and 13% lapatinib). Pazopanib offers great promise in treating cervical cancer because of its oral administration and the low incidence of serious toxicity. This is especially important because the majority of cervical cancer cases occur in the developing world and therapy for advanced and recurrent disease is heavily focused on palliation, which renders treatmentrelated severe side effects unacceptable. All reports of anti-angiogenesis agents in advanced and recurrent cervical cancer have not been as encouraging as the bevacizumab and pazopanib trials. The NCIC Canada Clinical Trials Group recently reported on a single-agent study of sunitinib malate, an oral, multitargeted TKI that inhibits VEGFR, c-Kit, and PDGFR among 19 patients with locally advanced or metastatic cervical carcinoma. Although 84% of those enrolled had stable disease (median duration, 4.4 months, 2.3–17 months), there were no objective responses and the median time to progression was 3.5 months (range, 2.7–7.0 months). Four patients developed fistulae on study treatment, and an additional patient developed a fistula 3.5 months after discontinuation of therapy. All five patients had received either prior chemoradiation or pelvic radiation alone [33]. This is quite concerning since gastrointestinal (GI) “perforation” is a known complication of this class of agents, but it is noteworthy that there was only one GI fistula in GOG 227C. Future directions and ongoing clinical trials Based on the success of bevacizumab in GOG 227C, a cohort of heavily pretreated patients, it seems logical to study this exciting new agent in conjunction with other first line therapies in stage IVB or
Fig. 4. Study design of VEG105281. Inclusion criteria included women with FIGO stage IVB, recurrent or persistent cervical cancer having received zero or one prior chemotherapy regimen for advanced/recurrent disease. Pazopanib (Paz) and lapatinib (Lap) are oral tyrosine kinase inhibitors that target VEGFR, PDGFR, and c-Kit, or EGFR and HER2, respectively. The primary endpoint was progression-free survival (PFS), and this study demonstrated the superiority of anti-angiogenesis therapy (Paz) compared to ant-EGF/HER2 (Lap) intervention. Secondary endpoints, response rate (ORR), and survival (OS) supported this conclusion (adopted from Monk et al. [32]).
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Fig. 5. Schema for Gynecologic Oncology Group protocol 240, a trial designed to evaluate four regimens against cervical cancer in a head-to-head fashion. This includes paclitaxel plus cisplatin, topotecan plus cisplatin, and both regimens with bevacizumab [33].
recurrent/persistent cervical carcinoma. However, the cost of bevacizumab and the limited availability of this agent in the developing world where cervical cancer is a common source of morbidity and mortality are a serious concern and deserve careful consideration. In addition, the cost-effectiveness of agents such as bevacizumab where only small increases in RR, PFS, and OS are realized requires future study although cheaper or generic alternatives may be available in the near future. GOG 240 is a study that involves randomization to one of four regimens: paclitaxel/cisplatin, paclitaxel/cisplatin plus bevacizumab, paclitaxel/topotecan, and paclitaxel/topotecan plus bevacizumab (Fig. 5) [34]. This study will evaluate OS from date of randomization and frequency and severity of adverse events as its primary endpoints. Secondary endpoints include PFS from date of randomization and frequency of objective tumor response. Because of the limited safety profile of these combinations, a carefully monitored safety plan is in place as well as an early assessment of toxicity. In addition to this phase III trial, other anti-angiogenesis compounds that target proangiogenesis factors other than VEGFR will soon be investigated by the GOG in the 227 protocol series. For example, brivanib, a highly potent dual inhibitor of VEGFR and fibroblast growth factor receptor (FGFR) and a member of a new class of pyrrolo[2,1-f]-1,2,4]triazinebased selective VEGFR-2 inhibitors, will soon be under study. Conclusion Angiogenesis is central to cervical cancer development and progression. The dominant role of angiogenesis in cervical cancer seems to be directly related to HPV inhibition of p53 and stabilization of HIF-1 alpha, both of which increase VEGF. The binding and inactivation of VEGF by bevacizumab seem to shrink cervical tumors
and delay progression without appreciable toxicity and are being studied in a GOG phase III trial. Other intracellular TKIs of angiogenesis such as pazopanib are also encouraging especially in lieu of their oral administration. Further study of angiogenesis and its inhibition is ongoing and represents one of the highest priorities in therapeutic gynecologic oncology today.
Conflict of interest statement There are no financial relationships and/or conflicts of interest between Dr. Willmott and Ms Sumner and the companies whose products are the subject of this article. Dr. Monk has received research funding from GlaxoSmithKline the maker of pazopanib.
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