Medical Oncology

, 34:115 | Cite as

Antiangiogenics and immunotherapies in cervical cancer: an update and future’s view

  • Daniela Luvero
  • Francesco Plotti
  • Salvatore Lopez
  • Giuseppe Scaletta
  • Stella Capriglione
  • Roberto Montera
  • Gianina Antonelli
  • Sara Ciuffreda
  • Raffaella Carassiti
  • Alice Oliveti
  • Roberto Angioli
Review Article


Despite availability of primary and secondary prevention measures, cervical cancer (CC) persists as one of the most common cancers among women around the world, and more than 70% of cases are diagnosed at advanced stages. Although significant progress has been made in the treatment of CC, around 15–61% of patients develop a recurrence in lymph nodes or distant sites within the first 2 years of completing treatment and the prognosis for these patients remains poor. During the last decades, in an attempt to improve the outcome in these patients, novel agents as combination therapy that target known dysfunctional molecular pathways have been developed with the most attention to the inhibitors of the angiogenesis process. One therapeutic target is the vascular endothelial growth factor, which has been shown to play a key role in tumor angiogenesis, not only for growth of new tissue but also in tumor proliferation. Bevacizumab is recognized as a potent antiangiogenic agent in ovarian cancer but has also demonstrated encouraging antitumor activity in recurrent CC. Moreover, other antiangiogenic agents were recently under study including: sunitinib, sorafenib, pazopanib, cediranib and nintedanib with interesting preliminary results. Moreover, over the last few years there has been increasing interest in cellular immunotherapy as a strategy to harness the immune system to fight tumors. This article focuses on recent discoveries about antiangiogenic agents and immunotherapies in the treatment of CC highlighting on future’s view.


Antiangiogenic therapies Cervical cancer Bevacizumab Pazopanib Immunotherapy Vaccines 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was not necessary because the study does not involve human participants


  1. 1.
    Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214(1):22–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN. Int J Cancer. 2012;136(2015):E359–86.Google Scholar
  3. 3.
    Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, et al. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999;340(15):1154–61.CrossRefPubMedGoogle Scholar
  4. 4.
    Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, et al. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999;340(15):1137–43.CrossRefPubMedGoogle Scholar
  5. 5.
    Peters WA, Liu PY, Barrett RGW. Cisplatin, 5-fluorouracil plus radiation therapy are superior to radiation therapy as adjunctive therapy in high risk, early stage carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: report of a phase III inter group study. Presented at Soc Gynecol Oncol 30th annual meeting, San Francisco, CA, 5–9 Feb, 1999; 1999.Google Scholar
  6. 6.
    Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, et al. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999;340(15):1144–53.CrossRefPubMedGoogle Scholar
  7. 7.
    Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, et al. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999;17(5):1339–48.CrossRefPubMedGoogle Scholar
  8. 8.
    Colombo N. Critical review of neoadjuvant chemotherapy followed by surgery for locally advanced cervical cancer. Int J Gynecol Cancer. 2010;20:S47–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Dishe S. Radiotherapy of cervical cancer. Clim Obstet. Gynecol. 12, 203—227. 17 (1985).Google Scholar
  10. 10.
    Barter JF, Soong SJ, Shingleton HM, Hatch KD. Orr JW’ Jr. Complications Of combined radical hysterectomy-postoperative radiation therapy in women with early stage cervical cancer. Gynecologic Oncol. 1989;32:292–6.CrossRefGoogle Scholar
  11. 11.
    Colombo N, Peiretti M. Critical review of neoadjuvant chemotherapy followed by surgery for locally advanced cervical cancer. Int J Gynecol Cancer. 2010;20(11 Suppl 2):S47–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Benedetti-Panici P, Greggi S, Colombo A, Amoroso M, Smaniotto D, Giannarelli D, Amunni G, Raspagliesi F, Zola P, Mangioni C, Landoni F. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol. 2002;20(1):179–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Rydzewska L, Tierney J, Vale CL, Symonds PR. Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev. 2012. doi: 10.1002/14651858.CD007406.pub3.
  14. 14.
    Sardi J, Sananes C. Neoadjuvant chemotherapy in cervical carcinoma stage IIB: a randomized controlled trial. Int J Gynecol Cancer. 1998;8:441–50.CrossRefGoogle Scholar
  15. 15.
    Chen H, Liang C, Zhang L, Huang S, Wu X. Clinical efficacy of modified preoperative neoadjuvant chemotherapy in the treatment of locally advanced (stage IB2 to IIB) cervical cancer: randomized study. Gynecol Oncol. 2008;110(3):308–15.CrossRefPubMedGoogle Scholar
  16. 16.
    Cho YH, Kim DY, Kim JH, Kim YM, Kim YT, Nam JH. Comparative study of neoadjuvant chemotherapy before radical hysterectomy and radical surgery alone in stage IB2-IIA bulky cervical cancer. J Gynecol Oncol. 2009;20(1):22–7.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Eddy GL, Bundy BN, Creasman WT, Spirtos NM, Mannel RS, Hannigan E, O’Connor D. Treatment of (“bulky”) stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the gynecologic oncology group. Gynecol Oncol. 2007;106(2):362–9 Epub 2007 May 9.CrossRefPubMedGoogle Scholar
  18. 18.
    Cai HB, Chen HZ, Yin HH. Randomized study of preoperative chemotherapy versus primary surgery for stage IB cervical cancer. J Obstet Gynaecol Res. 2006;32(3):315–23.CrossRefPubMedGoogle Scholar
  19. 19.
    Chang TC, Lai CH, Hong JH, Hsueh S, Huang KG, Chou HH, Tseng CJ, Tsai CS, Chang JT, Lin CT, Chang HH, Chao PJ, Ng KK, Tang SG, Soong YK. Randomized trial of neoadjuvant cisplatin, vincristine, bleomycin, and radical hysterectomy versus radiation therapy for bulky stage IB and IIA cervical cancer. J Clin Oncol. 2000;18(8):1740–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Vale Tierney JF, Stewart LA, et al. Chemoradiotherapy for cervical cancer meta-analysis collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J. Clin. Oncol. 2008;26:5802–12.CrossRefGoogle Scholar
  21. 21.
    Angioli R, Plotti F, Montera R, Aloisi A, Luvero D, Capriglione S, Terranova C, De Cicco Nardone C, Muzii L, Benedetti-Panici P. Neoadjuvant chemotherapy plus radical surgery followed by chemotherapy in locally advanced cervical cancer. Gynecol Oncol. 2012;127(2):290–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Angioli R, Luvero D, Aloisi A, Capriglione S, Gennari P, Linciano F, Li Destri M, Scaletta G, Montera R, Plotti F. Adjuvant chemotherapy after primary treatments for cervical cancer: a critical point of view and review of the literature. Expert Rev Anticancer Ther. 2014;14(4):431–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Angioli R, Plotti F, Aloisi A, Scaletta G, Capriglione S, Luvero D, Fiore L, Terranova C, Montera R, Panici PB. A randomized controlled trial comparing four versus six courses of adjuvant platinum-based chemotherapy in locally advanced cervical cancer patients previously treated with neo-adjuvant chemotherapy plus radical surgery. Gynecol Oncol. 2015;139(3):433–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Krill LS, Tewari KS. Integration of bevacizumab with chemotherapy doublets for advanced cervical cancer. Expert Opin Pharmacother. 2015;16(5):675–83.CrossRefPubMedGoogle Scholar
  25. 25.
    Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Brown LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995;26:86–91.CrossRefPubMedGoogle Scholar
  27. 27.
    Brown LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res. 1993;53:4727–35.PubMedGoogle Scholar
  28. 28.
    Guidi AJ, Abu-Jawdeh G, Tognazzi K, Dvorak HF, Brown LF. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in endometrial carcinoma. Cancer. 1996;7:454–60.CrossRefGoogle Scholar
  29. 29.
    Wimberger P, Chebouti I, Kasimir-Bauer S, et al. Explorative investigation of vascular endothelial growth factor receptor expression in primary ovarian cancer and its clinical relevance. Gynecol Oncol. 2014;133:467–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Wright JD, Viviano D, Powell MA, et al. Bevacizumab combination therapy in heavily pretreated, recurrent cervical cancer. Gynecol Oncol. 2006;103:489–93.CrossRefPubMedGoogle Scholar
  31. 31.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Schefter TE, Winter K, Kwon JS, et al. A phase II study of bevacizumab in combination with definitive radiotherapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma: preliminary results of RTOG 0417. Int J Radiat Oncol Biol Phys. 2012;83(1179–84):28.Google Scholar
  33. 33.
    Schefter T, Winter K, Kwon JS, et al. 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.CrossRefPubMedGoogle Scholar
  34. 34.
    Zighelboim I, Wright JD, Gao F, et al. Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer. Gynecol Oncol. 2013;130:64–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Tewari KS, Sill MW, Long HJ 3rd, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734–43.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mackay HJ, Tinker A, Winquist E, et al. 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.CrossRefPubMedGoogle Scholar
  37. 37.
    European Medicines Agency (2013). Avastin: summary of product characteristics.
  38. 38.
    Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427–34.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004;3:391–400.CrossRefPubMedGoogle Scholar
  40. 40.
    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.CrossRefPubMedGoogle Scholar
  41. 41.
    Penson RT, Huang HQ, Wenzel LB, Monk BJ, Stockman S, Long HJ 3rd, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Method M, Michael H, Tewari KS. Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet Oncol. 2015;16(3):301–11.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    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.CrossRefPubMedGoogle Scholar
  43. 43.
    Monk BJ, Pandite LN. Survival data from a phase II, open-label study of pazopanib or lapatinib monotherapy in patients with advanced and recurrent cervical cancer. J Clin Oncol. 2011;29:4845.CrossRefPubMedGoogle Scholar
  44. 44.
    Symonds RP, Gourley C, Davidson S, et al. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervix cancer (CIRCCa): A randomised, double blind, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16(15):1515–24.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Milosevic MF, Townsley CA, Chaudary N, Clarke B, Pintilie M, Fan S, Glicksman R, Haider M, Kim S, MacKay H, Yeung I, Hill RP, Fyles A, Oza AM. Sorafenib increases tumor hypoxia in cervical cancer patients treated with radiation therapy: results of a Phase 1 clinical study. Int J Radiat Oncol Biol Phys. 2016;94(1):111–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Schutz FA, Choueiri TK, Sternberg CN. Pazopanib. Clinical development of a potent anti-angiogenic drug. Crit Rev Oncol Hematol. 2011;77:163–71.CrossRefPubMedGoogle Scholar
  47. 47.
    Bellmunt J, Puente J, Garcia de Muro J, Lainez N, Rodríguez C, Duran I. SEOM clinical guidelines for the treatment of renal cell carcinoma. Clin Transl Oncol. 2014;16:1043–50.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Eskander RN, Tewari KS. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. Clin Ther. 2015;37:20–38.CrossRefPubMedGoogle Scholar
  49. 49.
    Callahan MK, Wolchok JD. At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. J Leukoc Biol. 2013;94:41–53.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Vici P, Mariani L, Pizzuti L, Sergi D, Di Lauro L, Vizza E, et al. Immunologic treatments for precancerous lesions and uterine cervical cancer. J Exp Clin Cancer Res. 2014;33:29.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, et al. Evidence for a role of the PD-1: PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res. 2013;73:1733–41.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Robert C, Ribas A, Wolchok JD, Hodi FS, Hamid O, Kefford R, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17.CrossRefPubMedGoogle Scholar
  54. 54.
    Tewari KS, Monk BJ. New strategies in advanced cervical cancer: from angiogenesis blockade to immunotherapy. Clin Cancer Res. 2014;20:5349–58.CrossRefPubMedGoogle Scholar
  55. 55.
    Joura EA, Giuliano AR, Iversen OE, Bouchard C, Mao C, Mehlsen J, Moreira ED Jr, Ngan Y, Petersen LK, Lazcano-Ponce E, Pitisuttithum P, Restrepo JA, Stuart G, Woelber L, Yang YC, Cuzick J, Garland SM, Huh W, Kjaer SK, Bautista OM, Chan IS, Chen J, Gesser R, Moeller E, Ritter M, Vuocolo S, Luxembourg A, Broad Spectrum HPV. Vaccine Study. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372(8):711–23.CrossRefPubMedGoogle Scholar
  56. 56.
    Angioli R, Lopez S, Aloisi A, Terranova C, De Cicco C, Scaletta G, Capriglione S, Miranda A, Luvero D, Ricciardi R, Montera R, Plotti F. Ten years of HPV vaccines: state of art and controversies. Crit Rev Oncol Hematol. 2016;102:65–72.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Daniela Luvero
    • 1
  • Francesco Plotti
    • 1
  • Salvatore Lopez
    • 1
  • Giuseppe Scaletta
    • 1
  • Stella Capriglione
    • 1
  • Roberto Montera
    • 1
  • Gianina Antonelli
    • 1
  • Sara Ciuffreda
    • 1
  • Raffaella Carassiti
    • 1
  • Alice Oliveti
    • 1
  • Roberto Angioli
    • 1
  1. 1.Department of Obstetrics and GynecologyUniversity of Rome “Campus Bio-Medico”RomeItaly

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