Elsevier

Gynecologic Oncology

Volume 116, Issue 2, February 2010, Pages 181-186
Gynecologic Oncology

Review
Anti-angiogenesis agents in metastatic or recurrent cervical cancer

https://doi.org/10.1016/j.ygyno.2009.09.033Get rights and content

Abstract

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.

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 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 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.

Section snippets

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

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

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

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 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

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

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.

References (34)

  • B.J. Monk et al.

    Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions

    J. Clin. Oncol.

    (2007)
  • Monk BJ. Gyncologic Oncology Group (GOG) Protocol 0204: a randomized phase III trial of paclitaxel plus cisplatin...
  • H.J. Long 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)
  • L.J. Willmott et al.

    Cervical cancer therapy: current, future and anti-angiogensis targeted treatment

    Expert Rev. Anticancer Ther.

    (2009)
  • R. Kerbel

    Tumor Angiogenesis

    N. Engl. J. Med.

    (2008)
  • G. Hopfl et al.

    HIFs and tumors—causes and consequences

    Am. J. Physiol., Regul. Integr. Comp. Physiol.

    (2004)
  • L.M. Brown et al.

    Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1

    Mol. Pharmacol.

    (2006)
  • Cited by (0)

    View full text