Skip to main content
SpringerLink
Log in

Advances in Cervical Cancer and Ongoing Clinical Trials

  • Chapter
  • First Online:
Gynecological Cancers

Part of the book series: Current Clinical Oncology ((CCO))

  • 762 Accesses

Abstract

The big issue in the fight against cancer is to understand the molecular mechanisms underlying the carcinogenesis process and try to direct the knowledge acquired in the direction of new and hopefully efficient therapies. In recent years, numerous studies have greatly implemented the knowledge about cervical cancer. It is well known that human papillomavirus (HPV) types cause approximately 90 % of cervical cancer. This evidence led the scientists to focus on HPV infection in relationship with cervical cancer, thereby developing vaccines for the prevention of cervical cancer. Screening with HPV testing was introduced around 1990, and prophylactic HPV vaccination was licensed in 2006. The synergistic effect of cancer prevention and early detection of cancers has been shown to improve survival rates and decrease mortality by timely appropriate treatment. Unfortunately, prophylactic vaccines are not able to eradicate established HPV infections and their associated tumor lesions. Advances have been made also in the clinical and therapeutic management of patients affected by cervical cancer. Important immunotherapeutic studies in advanced cervical cancer have been recently reported. In addition, various classes of anti-angiogenesis agents are studied with great interest in order to improve the efficacy of the treatment for patients with cervical carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

CIN:

Cervical intraepithelial neoplasia

DNMT:

DNA methyltransferase

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

ERK1:

Extracellular signal-regulated kinase 1

FGF:

Fibroblast growth factor

GOG:

Gynecologic Oncology Group

HDAC:

Histone deacetylase

HER2:

Human epidermal growth factor receptor 2

HPV:

Human papillomavirus

IFN:

Interferon

LNM:

Lymph node metastasis

MAPK1:

Mitogen-activated protein kinase 1

miRNA:

MicroRNA

NCCN:

National Comprehensive Cancer Network

NCI:

National Cancer Institute

NIP:

National Immunization Program

OS:

Overall survival

PD:

Programmed cell death

PD-L1:

Programmed cell death ligand 1

PFS:

Progression-free survival

PIK3CA:

Phosphatidylinositol-4 5-bisphosphate 3-kinase, catalytic subunit alpha

RTK:

Receptor tyrosine kinase

SCC:

Squamous cell carcinoma

TIL:

Tumor-infiltrating lymphocyte

VEGF:

Vascular endothelial growth factor

References

  1. Stewart B, Wild CP, editors. World cancer report 2014. Chapter 5.12: cancers of the female reproductive organs. Lyon: World Health Organization; 2014.

    Google Scholar 

  2. Giacinti C, Giordano A. RB and cell cycle progression. Oncogene. 2006;25:5220–7.

    Article  CAS  PubMed  Google Scholar 

  3. Hopman AH, Smedts F, Dignef W, Ummelen M, Sonke G, Mravunac M, Vooijs GP, Speel EJ, Ramaekers FC. Transition of high-grade cervical intraepithelial neoplasia to micro-invasive carcinoma is characterized by integration of HPV 16/18 and numerical chromosome abnormalities. J Pathol. 2004;202:23–33.

    Article  PubMed  Google Scholar 

  4. Nyagol J, Leucci E, Onnis A, De Falco G, Tigli C, Sanseverino F, Torriccelli M, Palummo N, Pacenti L, Santopietro R, et al. The effects of HIV-1 Tat protein on cell cycle during cervical carcinogenesis. Cancer Biol Ther. 2006;5:684–90.

    Article  CAS  PubMed  Google Scholar 

  5. Luhn P, Walker J, Schiffman M, Zuna RE, Dunn ST, Gold MA, Smith K, Mathews C, Allen RA, Zhang R, et al. The role of co-factors in the progression from human papillomavirus infection to cervical cancer. Gynecol Oncol. 2013;128:265–70.

    Article  CAS  PubMed  Google Scholar 

  6. Remschmidt C, Kaufmann AM, Hagemann I, Vartazarova E, Wichmann O, Delere Y. Risk factors for cervical human papillomavirus infection and high-grade intraepithelial lesion in women aged 20 to 31 years in Germany. Int J Gynecol Cancer. 2013;23:519–26.

    Article  PubMed  Google Scholar 

  7. Wang SS, Sherman ME, Hildesheim A, Lacey Jr JV, Devesa S. Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976–2000. Cancer. 2004;100:1035–44.

    Article  PubMed  Google Scholar 

  8. Galic V, Herzog TJ, Lewin SN, Neugut AI, Burke WM, Lu YS, Hershman DL, Wright JD. Prognostic significance of adenocarcinoma histology in women with cervical cancer. Gynecol Oncol. 2012;125:287–91.

    Article  PubMed  Google Scholar 

  9. Lee YY, Choi CH, Kim TJ, Lee JW, Kim BG, Lee JH, Bae DS. A comparison of pure adenocarcinoma and squamous cell carcinoma of the cervix after radical hysterectomy in stage IB-IIA. Gynecol Oncol. 2011;120:439–43.

    Article  PubMed  Google Scholar 

  10. Wright AA, Howitt BE, Myers AP, Dahlberg SE, Palescandolo E, Van Hummelen P, MacConaill LE, Shoni M, Wagle N, Jones RT, et al. Oncogenic mutations in cervical cancer: genomic differences between adenocarcinomas and squamous cell carcinomas of the cervix. Cancer. 2013;119:3776–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, Cherniack AD, Ambrogio L, Cibulskis K, Bertelsen B, et al. Landscape of genomic alterations in cervical carcinomas. Nature. 2014;506:371–5.

    Article  CAS  PubMed  Google Scholar 

  12. Yan M, Parker BA, Schwab R, Kurzrock R. HER2 aberrations in cancer: implications for therapy. Cancer Treat Rev. 2014;40:770–80.

    Article  CAS  PubMed  Google Scholar 

  13. Fadare O, Zheng W. HER2 protein (p185(HER2)) is only rarely overexpressed in cervical cancer. Int J Gynecol Pathol. 2004;23:410–1. author reply 411-412.

    Article  PubMed  Google Scholar 

  14. Jimenez-Wences H, Peralta-Zaragoza O, Fernandez-Tilapa G. Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review). Oncol Rep. 2014;31:2467–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Pedroza-Torres A, Lopez-Urrutia E, Garcia-Castillo V, Jacobo-Herrera N, Herrera LA, Peralta-Zaragoza O, Lopez-Camarillo C, De Leon DC, Fernandez-Retana J, Cerna-Cortes JF, et al. MicroRNAs in cervical cancer: evidences for a miRNA profile deregulated by HPV and its impact on radio-resistance. Molecules. 2014;19:6263–81.

    Article  PubMed  Google Scholar 

  16. Wang WT, Zhao YN, Yan JX, Weng MY, Wang Y, Chen YQ, Hong SJ. Differentially expressed microRNAs in the serum of cervical squamous cell carcinoma patients before and after surgery. J Hematol Oncol. 2014;7:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu J, Wang Y, Dong R, Huang X, Ding S, Qiu H. Circulating microRNA-218 was reduced in cervical cancer and correlated with tumor invasion. J Cancer Res Clin Oncol. 2012;138:671–4.

    Article  CAS  PubMed  Google Scholar 

  18. Zhao S, Yao D, Chen J, Ding N. Circulating miRNA-20a and miRNA-203 for screening lymph node metastasis in early stage cervical cancer. Genet Test Mol Biomarkers. 2013;17:631–6.

    Article  CAS  PubMed  Google Scholar 

  19. Chen J, Yao D, Li Y, Chen H, He C, Ding N, Lu Y, Ou T, Zhao S, Li L, et al. Serum microRNA expression levels can predict lymph node metastasis in patients with early-stage cervical squamous cell carcinoma. Int J Mol Med. 2013;32:557–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21.

    Article  CAS  PubMed  Google Scholar 

  21. Wilting SM, van Boerdonk RA, Henken FE, Meijer CJ, Diosdado B, Meijer GA, le Sage C, Agami R, Snijders PJ, Steenbergen RD. Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer. Mol Cancer. 2010;9:167.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Saavedra KP, Brebi PM, Roa JC. Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. Clin Epigenet. 2012;4:13.

    Article  CAS  Google Scholar 

  23. Rouhi A, Mager DL, Humphries RK, Kuchenbauer F. MiRNAs, epigenetics, and cancer. Mamm Genome. 2008;19:517–25.

    Article  CAS  PubMed  Google Scholar 

  24. Bock C. Epigenetic biomarker development. Epigenomics. 2009;1:99–110.

    Article  CAS  PubMed  Google Scholar 

  25. Lopez-Serra P, Esteller M. DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene. 2012;31:1609–22.

    Article  CAS  PubMed  Google Scholar 

  26. Yao T, Rao Q, Liu L, Zheng C, Xie Q, Liang J, Lin Z. Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in cervical cancer. Virol J. 2013;10:175.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wilting SM, Verlaat W, Jaspers A, Makazaji NA, Agami R, Meijer CJ, Snijders PJ, Steenbergen RD. Methylation-mediated transcriptional repression of microRNAs during cervical carcinogenesis. Epigenetics. 2013;8:220–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Botezatu A, Goia-Rusanu CD, Iancu IV, Huica I, Plesa A, Socolov D, Ungureanu C, Anton G. Quantitative analysis of the relationship between microRNA124a, -34b and -203 gene methylation and cervical oncogenesis. Mol Med Rep. 2011;4:121–8.

    CAS  PubMed  Google Scholar 

  29. Au Yeung CL, Tsang WP, Tsang TY, Co NN, Yau PL, Kwok TT. HPV-16 E6 upregulation of DNMT1 through repression of tumor suppressor p53. Oncol Rep. 2010;24:1599–604.

    PubMed  Google Scholar 

  30. zur Hausen H. Human papillomaviruses and their possible role in squamous cell carcinomas. Curr Top Microbiol Immunol. 1977;78:1–30.

    CAS  PubMed  Google Scholar 

  31. Franco EL, Harper DM. Vaccination against human papillomavirus infection: a new paradigm in cervical cancer control. Vaccine. 2005;23:2388–94.

    Article  CAS  PubMed  Google Scholar 

  32. Bermudez-Humaran LG, Langella P. Perspectives for the development of human papillomavirus vaccines and immunotherapy. Expert Rev Vaccines. 2010;9:35–44.

    Article  PubMed  Google Scholar 

  33. Markowitz LE, Tsu V, Deeks SL, Cubie H, Wang SA, Vicari AS, Brotherton JM. Human papillomavirus vaccine introduction—the first five years. Vaccine. 2012;30 Suppl 5:F139–48.

    Article  PubMed  Google Scholar 

  34. D'Andrilli G, Bovicelli A, Giordano A. HPV vaccines: state of the art. J Cell Physiol. 2010;224:601–4.

    Article  PubMed  Google Scholar 

  35. Hakim AA, Dinh TA. Worldwide impact of the human papillomavirus vaccine. Curr Treat Options Oncol. 2009;10:44–53.

    Article  PubMed  Google Scholar 

  36. Arbyn M, Dillner J. Review of current knowledge on HPV vaccination: an appendix to the European guidelines for quality assurance in cervical cancer screening. J Clin Virol. 2007;38:189–97.

    Article  PubMed  Google Scholar 

  37. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.

    Article  CAS  PubMed  Google Scholar 

  38. Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Monk BJ, Chan JK. American Society of Clinical Oncology. Annual meeting update: summary of selected gynecologic cancer abstracts. Gynecol Oncol. 2010;2010(118):216–9.

    Google Scholar 

  40. Tewari KS, Sill MW, Long 3rd HJ, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. NCI Press Release: Bevacizumab significantly improves survival for patients with recurrent and metastatic cervical cancer [Internet]. 2013. http://www.cancer.gov/news-events/press-releases/2013/GOG240.

  42. Tewari KS. American Society of Clinical Oncology. Annual meeting: highlights from the gynecologic oncology track. Int J Gynecol Cancer. 2012;2012(22):1634–9.

    Google Scholar 

  43. Karim R, Jordanova ES, Piersma SJ, Kenter GG, Chen L, Boer JM, Melief CJ, van der Burg SH. Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res. 2009;15:6341–7.

    Article  CAS  PubMed  Google Scholar 

  44. Radulovic S, Brankovic-Magic M, Malisic E, Jankovic R, Dobricic J, Plesinac-Karapandzic V, Maciag PC, Rothman J. Therapeutic cancer vaccines in cervical cancer: phase I study of Lovaxin-C. J BUON. 2009;14 Suppl 1:S165–8.

    PubMed  Google Scholar 

  45. Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. 2014;257:56–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Baleja JD, Cherry JJ, Liu Z, Gao H, Nicklaus MC, Voigt JH, Chen JJ, Androphy EJ. Identification of inhibitors to papillomavirus type 16 E6 protein based on three-dimensional structures of interacting proteins. Antiviral Res. 2006;72:49–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Liu Y, Liu Z, Androphy E, Chen J, Baleja JD. Design and characterization of helical peptides that inhibit the E6 protein of papillomavirus. Biochemistry. 2004;43:7421–31.

    Article  CAS  PubMed  Google Scholar 

  48. Zehbe I, Richard C, Lee KF, Campbell M, Hampson L, Hampson IN. Lopinavir shows greater specificity than zinc finger ejecting compounds as a potential treatment for human papillomavirus-related lesions. Antiviral Res. 2011;91:161–6.

    Article  CAS  PubMed  Google Scholar 

  49. Van Pachterbeke C, Bucella D, Rozenberg S, Manigart Y, Gilles C, Larsimont D, Vanden Houte K, Reynders M, Snoeck R, Bossens M. Topical treatment of CIN 2+ by cidofovir: results of a phase II, double-blind, prospective, placebo-controlled study. Gynecol Oncol. 2009;115:69–74.

    Article  PubMed  Google Scholar 

  50. Montes L, Andrade CM, Michelin MA, Murta EF. The importance of alpha/beta (alpha/13) interferon receptors and signaling pathways for the treatment of cervical intraepithelial neoplasias. Eur J Gynaecol Oncol. 2014;35:368–72.

    CAS  PubMed  Google Scholar 

  51. Kim SH, Cohen B, Novick D, Rubinstein M. Mammalian type I interferon receptors consists of two subunits: IFNaR1 and IFNaR2. Gene. 1997;196:279–86.

    Article  CAS  PubMed  Google Scholar 

  52. Moraga I, Harari D, Schreiber G, Uze G, Pellegrini S. Receptor density is key to the alpha2/beta interferon differential activities. Mol Cell Biol. 2009;29:4778–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Machado FA, Abdalla DR, Montes L, Etchebehere RM, Michelin MA, Murta EF. An evaluation of immune system cell infiltrate in the cervical stroma of patients with grade III cervical intraepithelial neoplasia after treatment with intralesional alpha-2B interferon. Eur J Gynaecol Oncol. 2014;35:20–5.

    CAS  PubMed  Google Scholar 

  54. Hashimoto I, Kodama J, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T. Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer. 2001;85:93–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lee JS, Kim HS, Jung JJ, Lee MC, Park CS. Expression of vascular endothelial growth factor in adenocarcinomas of the uterine cervix and its relation to angiogenesis and p53 and c-erbB-2 protein expression. Gynecol Oncol. 2002;85:469–75.

    Article  CAS  PubMed  Google Scholar 

  56. del Campo JM, Prat A, Gil-Moreno A, Perez J, Parera M. Update on novel therapeutic agents for cervical cancer. Gynecol Oncol. 2008;110:S72–6.

    Article  PubMed  Google Scholar 

  57. Mathur RS, Mathur SP. Vascular endothelial growth factor (VEGF) up-regulates epidermal growth factor receptor (EGF-R) in cervical cancer in vitro: this action is mediated through HPV-E6 in HPV-positive cancers. Gynecol Oncol. 2005;97:206–13.

    Article  CAS  PubMed  Google Scholar 

  58. Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther. 2006;28:1779–802.

    Article  CAS  PubMed  Google Scholar 

  59. Kunos CA, Sherertz TM. Long-term disease control with triapine-based radiochemotherapy for patients with stage IB2-IIIB cervical cancer. Front Oncol. 2014;4:184.

    Article  PubMed  PubMed Central  Google Scholar 

  60. de la Cruz-Hernandez E, Perez-Cardenas E, Contreras-Paredes A, Cantu D, Mohar A, Lizano M, Duenas-Gonzalez A. The effects of DNA methylation and histone deacetylase inhibitors on human papillomavirus early gene expression in cervical cancer, an in vitro and clinical study. Virol J. 2007;4:18.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Lin Z, Bazzaro M, Wang MC, Chan KC, Peng S, Roden RB. Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res. 2009;15:570–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, Gonzalez-Fierro A, de la Cruz-Hernandez E, Perez-Cardenas E, Taja-Chayeb L, Arias-Bofill D, Candelaria M, et al. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer preliminary results. Med Oncol. 2011;28 Suppl 1:540–6.

    Article  CAS  Google Scholar 

  63. Moktar A, Singh R, Vadhanam MV, Ravoori S, Lillard JW, Gairola CG, Gupta RC. Cigarette smoke condensate-induced oxidative DNA damage and its removal in human cervical cancer cells. Int J Oncol. 2011;39:941–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Beevi SS, Rasheed MH, Geetha A. Evidence of oxidative and nitrosative stress in patients with cervical squamous cell carcinoma. Clin Chim Acta. 2007;375:119–23.

    Article  CAS  PubMed  Google Scholar 

  65. Di Domenico F, Foppoli C, Coccia R, Perluigi M. Antioxidants in cervical cancer: chemopreventive and chemotherapeutic effects of polyphenols. Biochim Biophys Acta. 1822;2012:737–47.

    Google Scholar 

  66. Fuchs-Tarlovsky V, Rivera MA, Altamirano KA, Lopez-Alvarenga JC, Ceballos-Reyes GM. Antioxidant supplementation has a positive effect on oxidative stress and hematological toxicity during oncology treatment in cervical cancer patients. Support Care Cancer. 2013;21:1359–63.

    Article  PubMed  Google Scholar 

  67. Vici P, Mariani L, Pizzuti L, Sergi D, Di Lauro L, Vizza E, Tomao F, Tomao S, Mancini E, Vincenzoni C, et al. Emerging biological treatments for uterine cervical carcinoma. J Cancer. 2014;5:86–97.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  69. Mackay HJ, Tinker A, Winquist E, Thomas G, Swenerton K, Oza A, Sederias J, Ivy P, Eisenhauer EA. A phase II study of sunitinib in patients with locally advanced or metastatic cervical carcinoma: NCIC CTG Trial IND.184. Gynecol Oncol. 2010;116:163–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biology, College of Science and Technology, Temple University, 1900 N 12th Street, Biolife Science Bld, Philadelphia, PA, 19122, USA

    Giuseppina D’Andrilli PhD

Authors
  1. Giuseppina D’Andrilli PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giuseppina D’Andrilli PhD .

Editor information

Editors and Affiliations

  1. Department of Biology, Temple University, Philadelphia, Pennsylvania, USA

    Antonio Giordano

  2. Department of Biology, Temple University, Philadelphia, Pennsylvania, USA

    Marcella Macaluso

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

D’Andrilli, G. (2016). Advances in Cervical Cancer and Ongoing Clinical Trials. In: Giordano, A., Macaluso, M. (eds) Gynecological Cancers. Current Clinical Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-32907-9_3

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-32907-9_3

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-32905-5

  • Online ISBN: 978-3-319-32907-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation