Advertisement

Management of Recurrent Uterine Cervical Cancer

  • George Zarkavelis
  • Alexandra Papadaki
  • Aristides Kefas
  • Ioannis Zerdes
  • Konstantina Tatsi
  • Stergios Boussios
Chapter

Abstract

Although primary and secondary prevention strategies are widely applied, a significant number of women will develop recurrent or metastatic cervical cancer. In addition, 5% of newly diagnosed cervical cancers of the uterus are already metastatic. The established platinum-based chemotherapy remains the gold standard for advanced stages, but the prognosis still remains dismal. There is an increasing need for the use of new agents taking into consideration that since bevacizumab was approved in first-line treatment, no further progress in terms of therapeutic options has been achieved. Furthermore, the administration of bevacizumab, due to subsequent patients’ survival prolongation, will ultimately lead to a greater number of women to the point of second or even further line therapy administration.

Besides platinums other chemotherapy agents that have shown efficacy in recurrent or metastatic cervical cancer include vinca alkaloids, taxanes, topoisomerase inhibitors, alkylating agents, and antimetabolites. Clinical trials evaluating the role of anti-EGFR monoclonal antibodies, tyrosine kinase inhibition, mTOR-targeted molecules, and therapeutic vaccines have been conducted indicating that more research needs to be conducted in large-scale trials. Taking into consideration the established association between cervical cancer and HPV infection, there is a trend toward the evaluation of possible benefit with the use of immunomodulatory agents such as anti-CTLA4 and anti-PD-1/PD-L1 which are able of activating the immune system by reversing immune-evading mechanisms.

The existing limitations in the therapeutic armory of metastatic cervical cancer can be overcome through further investigation and encouragement for participation in clinical trials in order to prolong patient’s survival in terms of enhanced quality of life (Fig. 11.1).
Fig. 11.1

Therapeutic landscape of recurrent cervical cancer

Keywords

Cervical cancer Chemotherapy for cervical cancer Metastatic cervical cancer Recurrent cervical cancer Targeted therapy for cervical cancer 

References

  1. 1.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Pimple S, Mishra G, Shastri S. Global strategies for cervical cancer prevention. Curr Opin Obstet Gynecol. 2016;28:4–10.PubMedCrossRefGoogle Scholar
  3. 3.
    Bryan JT, Buckland B, Hammond J, Jansen KU. Prevention of cervical cancer: journey to develop the first human papillomavirus virus-like particle vaccine and the next generation vaccine. Curr Opin Chem Biol. 2016;32:34–47.PubMedCrossRefGoogle Scholar
  4. 4.
    Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214(1):22–30.CrossRefGoogle Scholar
  5. 5.
    Li H, Wu X, Cheng X. Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol. 2016;27(4):e43.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Quinn MA, Benedet JL, Odicino F, Maisonneuve P, Beller U, Creasman WT, Heintz AP, Ngan HY, Pecorelli S. Carcinoma of the cervix uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006;95(Suppl 1):S43–103.PubMedCrossRefGoogle Scholar
  7. 7.
    Dornhöfer N, Höckel M. New developments in the surgical therapy of cervical carcinoma. Ann N Y Acad Sci. 2008;1138:233–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Zola P, Fuso L, Mazzola S, Piovano E, Perotto S, Gadducci A, Galletto L, Landoni F, Maggino T, Raspagliesi F, Sartori E, Scambia G. Could follow-up different modalities play a role in asymptomatic cervical cancer relapses diagnosis? An Italian multicenter retrospective analysis. Gynecol Oncol. 2007;107(1 Suppl 1):S150–4.CrossRefGoogle Scholar
  9. 9.
    Perez CA, Grigsby PW, Camel HM, Galakatos AE, Mutch D, Lockett MA. Irradiation alone or combined with surgery in stage IB, IIA, and IIB carcinoma of uterine cervix: update of a nonrandomized comparison. Int J Radiat Oncol Biol Phys. 1995;31(4):703–16.PubMedCrossRefGoogle Scholar
  10. 10.
    Piura B, Rabinovich A, Friger M. Recurrent cervical carcinoma after radical hysterectomy and pelvic lymph node dissection: a study of 32 cases. Eur J Gynaecol Oncol. 2008;29(1):31–6.PubMedGoogle Scholar
  11. 11.
    Friedlander M, Grogan M, U.S. Preventative Services Task Force. Guidelines for the treatment of recurrent and metastatic cervical cancer. Oncologist. 2002;7(4):342–7.Google Scholar
  12. 12.
    Goldberg GL, Sukumvanich P, Einstein MH, Smith HO, Anderson PS, Fields AL. Total pelvic exenteration: the Albert Einstein College of Medicine/Montefiore Medical Center Experience (1987 to 2003). Gynecol Oncol. 2006;101(2):261–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Fleisch MC, Pantke P, Beckmann MW, Schnuerch HG, Ackermann R, Grimm MO, Bender HG, Dall P. Predictors for long-term survival after interdisciplinary salvage surgery for advanced or recurrent gynecologic cancers. J Surg Oncol. 2007;95(6):476–84.PubMedCrossRefGoogle Scholar
  14. 14.
    Panici PB, Angioli R, Plotti F, Muzii L, Zullo MA, Manci N, Palaia I, Galluci M. Continent ileocolonic urinary diversion (Rome pouch) for gynecologic malignancies: technique and feasibility. Gynecol Oncol. 2007;107(2):194–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Jover R, Lourido D, Gonzalez C, Rojo A, Gorospe L, Alfonso JM. Role of PET/CTin the evaluation of cervical cancer. Gynecol Oncol. 2008;110(3 Suppl 2):S55–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Green AE, Escobar PF, Neubaurer N, Michener CM, Vongruenigen VE. The Martius flap neovagina revisited. Int J Gynecol Cancer. 2005;15(5):964–6.PubMedCrossRefGoogle Scholar
  17. 17.
    Lopez-Graniel C, Dolores R, Cetina L, Gonzalez A, Cantu D, Chanona J, Uribe J, Candelaria M, Brom R, de la Garza J, Duenas-Gonzalez A. Pre-exenterative chemotherapy, a novel therapeutic approach for patients with persistent or recurrent cervical cancer. BMC Cancer. 2005;5:118.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Höckel M. Laterally extended endopelvic resection (LEER) – principles and practice. Gynecol Oncol. 2008;111(2 Suppl):S13–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Singh AK, Grigsby PW, Rader JS, Mutch DG, Powell MA. Cervix carcinoma, concurrent chemoradiotherapy, and salvage of isolated paraaortic lymph node recurrence. Int J Radiat Oncol Biol Phys. 2005;61(2):450–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Chou HH, Wang CC, Lai CH, Hong JH, Ng KK, Chang TC, Tseng CJ, Tsai CS, Chang JT. Isolated paraaortic lymph node recurrence after definitive irradiation for cervical carcinoma. Int J Radiat Oncol Biol Phys. 2001;51(2):442–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Muderspach LI, Blessing JA, Levenback C, Moore JL Jr. A phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2001;81(2):213–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Kudelka AP, Winn R, Edwards CL, Downey G, Greenberg H, Dakhil SR, Freedman RS, LoCoco S, Umbreit J, Delmore JE, Arbuck S, Loyer E, Gacrama P, Fueger R, Kavanagh JJ. An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Anti-Cancer Drugs. 1997;8(7):657–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Garcia AA, Blessing JA, Vaccarello L, Roman LD, Gynecologic Oncology Group Study. Gynecologic Oncology Group study: phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 2007;30(4):428–31.PubMedCrossRefGoogle Scholar
  24. 24.
    Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2005;96(1):103–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Muggia FM, Blessing JA, Waggoner S, Berek JS, Monk BJ, Sorosky J, Pearl ML. Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2005;96(1):108–11.PubMedCrossRefGoogle Scholar
  26. 26.
    Lhommé C, Fumoleau P, Fargeot P, Krakowski Y, Dieras V, Chauvergne J, Vennin P, Rebattu P, Roche H, Misset JL, Lentz MA, Van Glabbeke M, Matthieu-Boué A, Mignard D, Chevallier B. Results of a European Organization for Research and Treatment of Cancer/Early Clinical Studies Group phase II trial of first-line irinotecan in patients with advanced or recurrent squamous cell carcinoma of the cervix. J Clin Oncol. 1999;17(10):3136–42.PubMedCrossRefGoogle Scholar
  27. 27.
    Sutton GP, Blessing JA, DiSaia PJ, McGuire WP. Phase II study of ifosfamide and mesna in nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1993;49(1):48–50.PubMedCrossRefGoogle Scholar
  28. 28.
    Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J, Miller DS, Eaton LA, Fiorica JV, Gynecologic Oncology Group Study. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2005;23(21):4626–33.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009;27(28):4649–55.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Miller DS, Blessing JA, Ramondetta LM, Pham HQ, Tewari KS, Landrum LM, Brown J, Mannel RS. Pemetrexed and cisplatin for the treatment of advanced, persistent, or recurrent carcinoma of the cervix: a limited access phase II trial of the Gynecologic Oncology Group. J Clin Oncol. 2014;32(25):2744–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bloss JD, Blessing JA, Behrens BC, Mannel RS, Rader JS, Sood AK, Markman M, Benda J. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2002;20(7):1832–7.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Choi CH, Kim TJ, Lee SJ, Lee JW, Kim BG, Lee JH, Bae DS. Salvage chemotherapy with a combination of paclitaxel, ifosfamide, and cisplatin for the patients with recurrent carcinoma of the uterine cervix. Int J Gynecol Cancer. 2006;16(3):1157–64.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    van Luijk IF, Coens C, van der Burg ME, Kobierska A, Namer M, Lhomme C, Zola P, Zanetta G, Vermorken JB, Gynecological Cancer Group of the European Organization for Research and Treatment of Cancer. Phase II study of bleomycin, vindesine, mitomycin C and cisplatin (BEMP) in recurrent or disseminated squamous cell carcinoma of the uterine cervix. Ann Oncol. 2007;18(2):275–81.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734–43.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J, Miller DS, Olt G, King S, Boggess JF, Rocereto TF. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2004;22(15):3113–9.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, Nishimura S, Ushijima K, Takano M, Satoh T, Yoshikawa H. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015;33(19):2129–35.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Zanetta G, Fei F, Parma G, Balestrino M, Lissoni A, Gabriele A, Mangioni C. Paclitaxel, ifosfamide and cisplatin (TIP) chemotherapy for recurrent or persistent squamous-cell cervical cancer. Ann Oncol. 1999;10(10):1171–4.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Dimopoulos MA, Papadimitriou CA, Sarris K, Aravantinos G, Kalofonos C, Gika D, Gourgoulis GM, Efstathiou E, Skarlos D, Bafaloukos D. Combination of ifosfamide, paclitaxel, and cisplatin for the treatment of metastatic and recurrent carcinoma of the uterine cervix: a phase II study of the Hellenic Cooperative Oncology Group. Gynecol Oncol. 2002;85(3):476–82.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Omura GA, Blessing JA, Vaccarello L, Berman ML, Clarke-Pearson DL, Mutch DG, Anderson B. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997;15(1):165–71.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Vermorken JB, Zanetta G, De Oliveira CF, van der Burg ME, Lacave AJ, Teodorovic I, Boes GH, Colombo N. Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study. Ann Oncol. 2001;12(7):967–74.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Mannel RS, Blessing JA, Boike G. Cisplatin and pentoxifylline in advanced or recurrent squamous cell carcinoma of the cervix: a phase II trial of the Gynecologic Oncology Group. Gynecol Oncol. 2000;79(1):64–6.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Vermorken JB, Mangioni C, Pecorelli S, Van Der Burg ME, Van Oosterom AT, Ten Bokkel Huinink WW, Rotmensz N, Dalesio O. Phase II study of vincristine, bleomycin, mitomycin C and cisplatin (VBMP) in disseminated squamous cell carcinoma of the uterine cervix. Int J Gynecol Cancer. 2000;10(5):358–65.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Wagenaar HC, Pecorelli S, Mangioni C, van der Burg ME, Rotmensz N, Anastasopoulou A, Zola P, Veenhof CH, Lacave AJ, Neijt JP, van Oosterom AT, Einhorn N, Vermorken JB. Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix. A European Organization for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study. Eur J Cancer. 2001;37(13):1624–8.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Miller DS, Tai DF, Obasaju C, Vergote I. Safety and efficacy of pemetrexed in gynecologic cancers: a systematic literature review. Mod Chemother. 2013;2:19–32.CrossRefGoogle Scholar
  45. 45.
    Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Malzoni C, Sartori E, Scollo P, Torri V, Zola P, Mangioni C. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide, and cisplatin with ifosfamide and cisplatin followed by radical surgery in patients with locally advanced squamous cell cervical carcinoma: the SNAP01 (Studio Neo-Adjuvante Portio) Italian Collaborative Study. J Clin Oncol. 2005;23(18):4137–45.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Schilder RJ, Blessing JA, Morgan M, Mangan CE, Rader JS. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000;76(2):204–7.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Sutton GP, Blessing JA, Adcock L, Webster KD, DeEulis T. Phase II study of ifosfamide and mesna in patients with previously-treated carcinoma of the cervix. A Gynecologic Oncology Group study. Investig New Drugs. 1989;7(4):341–3.CrossRefGoogle Scholar
  48. 48.
    Verschraegen CF, Levy T, Kudelka AP, Llerena E, Ende K, Freedman RS, Edwards CL, Hord M, Steger M, Kaplan AL, Kieback D, Fishman A, Kavanagh JJ. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol. 1997;15(2):625–31.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Look KY, Blessing JA, Michener CM, Rubin S, Ramirez PT, Gynecologic Oncology Group Study. Phase II evaluation of capecitabine in refractory nonsquamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Int J Gynecol Cancer. 2008;18(4):773–8.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Lorvidhaya V, Chitapanarux I, Phromratanapongse P, Kamnerdsupaphon P, Tharavichitkul E, Lertsanguansinchai P, Hsieh CY, Sukthomya V. Phase II study of capecitabine (Ro 09-1978) in patients who have failed first line treatment for locally advanced and/or metastatic cervical cancer. Gan To Kagaku Ryoho. 2010;37(7):1271–5.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Katsumata N, Hirai Y, Kamiura S, Sugiyama T, Kokawa K, Hatae M, Nishimura R, Ochiai K. Phase II study of S-1, an oral fluoropyrimidine, in patients with advanced or recurrent cervical cancer. Ann Oncol. 2011;22(6):1353–7.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Coronel J, Cetina L, Candelaria M, González-Fierro A, Arias D, Cantu D, Dueñas-González A. Weekly topotecan as second- or third-line treatment in patients with recurrent or metastatic cervical cancer. Med Oncol. 2009;26(2):210–4.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Fiorica JV, Blessing JA, Puneky LV, Secord AA, Hoffman JS, Yamada SD, Buekers TE, Bell J, Schilder JM, Gynecologic Oncology Group. A phase II evaluation of weekly topotecan as a single agent second line therapy in persistent or recurrent carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2009;115(2):285–9.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Lorusso D, Ferrandina G, Pignata S, Ludovisi M, Viganò R, Scalone S, Scollo P, Breda E, Pietragalla A, Scambia G. Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group. Ann Oncol. 2010;21(1):61–6.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Thigpen T. The role of chemotherapy in the management of carcinoma of the cervix. Cancer J. 2003;9(5):425–32.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Takeuchi S, Dobashi K, Fujimoto S, Tanaka K, Suzuki M, Terashima Y, Hasumi K, Akiya K, Negishi Y, Tamaya T, et al. A late phase II study of CPT-11 on uterine cervical cancer and ovarian cancer. Research Groups of CPT-11 in Gynecologic Cancers. Gan To Kagaku Ryoho. 1991;18(10):1681–9.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Garcia AA, Blessing JA, Darcy KM, Lenz HJ, Zhang W, Hannigan E, Moore DH. Phase II clinical trial of capecitabine in the treatment of advanced, persistent or recurrent squamous cell carcinoma of the cervix with translational research: a Gynecologic Oncology Group study. Gynecol Oncol. 2007;104(3):572–9.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA. Topotecan in squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000;77(3):446–9.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Noda K, Sasaki H, Yamamoto K, Yamamoto T, Nishimura R, Sugiyama T, et al. Phase II trial of topotecan for cervical cancer of the uterus. Proc Am Soc Clin Oncol. 1996;15:280.Google Scholar
  60. 60.
    Abu-Rustum NR, Lee S, Massad LS. Topotecan for recurrent cervical cancer after platinum-based therapy. Int J Gynecol Cancer. 2000;10(4):285–8.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Nascimento de Oliveira L, Guerra Alves FV, Ribeiro Mora PA, Calazan do Carmo C, Nogueira-Rodrigues A, Ingles Garces AH, et al. Topotecan use for second-line treatment in patients with recurrent or metastatic cervical cancer at Brazilian National Cancer Institute (INCA). JCT. 2013;4(6):1095–9.CrossRefGoogle Scholar
  62. 62.
    Muggia FM, Blessing JA, Method M, Miller DS, Johnson GA, Lee RB, Menzin A, Gynecologic Oncology Group study. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(2):639–43.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Miller DS, Blessing JA, Bodurka DC, Bonebrake AJ, Schorge JO, Gynecologic Oncology Group. Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2008;110(1):65–70.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Thigpen T, Shingleton H, Homesley H, Lagasse L, Blessing J. Cis-platinum in treatment of advanced or recurrent squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Cancer. 1981;48(4):899–903.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Rose PG, Blessing JA, Lele S, Abulafia O. Evaluation of pegylated liposomal doxorubicin (Doxil) as second-line chemotherapy of squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2006;102(2):210–3.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Rose PG, Blessing JA, Arseneau J. Phase II evaluation of altretamine for advanced or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1996;62(1):100–2.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Rose PG, Blessing JA, Van Le L, Waggoner S. Prolonged oral etoposide in recurrent or advanced squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1998;70(2):263–6.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Curtin JP, Blessing JA, Webster KD, Rose PG, Mayer AR, Fowler WC Jr, Malfetano JH, Alvarez RD. Paclitaxel, an active agent in nonsquamous carcinomas of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2001;19(5):1275–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Vermorken JB, Tumolo S, Roozendaal KJ, Guastalla JP, Splinter TA, Renard J. 5-aza-2’-deoxycytidine in advanced or recurrent cancer of the uterine cervix. Eur J Cancer. 1991;27(2):216–7.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    van der Burg ME, Monfardini S, Guastalla JP, de Oliveira C, Renard J, Vermorken JB. Phase II study of weekly 4’-epidoxorubicin in patients with metastatic squamous cell cancer of the cervix: an EORTC Gynaecological Cancer Cooperative Group study. Eur J Cancer. 1992;29A(1):147–8.PubMedGoogle Scholar
  71. 71.
    ClinicalTrials.gov. Phase III study of S-1 + cisplatin vs cisplatin in cervical cancer. NCT00770874.Google Scholar
  72. 72.
    McLachlan J, Boussios S, Okines A, Glaessgen D, Bodlar S, Kalaitzaki R, Taylor A, Lalondrelle S, Gore M, Kaye S, Banerjee S. The impact of systemic therapy beyond first-line treatment for advanced cervical cancer. Clin Oncol (R Coll Radiol). 2017;29(3):153–60.CrossRefGoogle Scholar
  73. 73.
    Manders DB, Kehoe SM, Miller DS, Lea JS, Richardson DL. Third-line salvage chemotherapy for recurrent carcinoma of the cervix is associated with minimal response rate and high toxicity. Am J Clin Oncol. 2017; [Epub ahead of print].Google Scholar
  74. 74.
    Tewari KS, Monk BJ. The rationale for the use of non-platinum chemotherapy doublets for metastatic and recurrent cervical carcinoma. Clin Adv Hematol Oncol. 2010;8(2):108–15.PubMedGoogle Scholar
  75. 75.
    Tang X, Zhang Q, Nishitani J, Brown J, Shi S, Le AD. Overexpression of human papillomavirus type 16 oncoproteins enhances hypoxia-inducible factor 1 alpha protein accumulation and vascular endothelial growth factor expression in human cervical carcinoma cells. Clin Cancer Res. 2007;13(9):2568–76.CrossRefGoogle Scholar
  76. 76.
    Look KY, Blessing JA, Gallup DG, Lentz SS. A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 1996;19(5):439–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Look KY, Blessing JA, Nelson BE, Johnson GA, Fowler WC Jr, Reid GC. A phase II trial of isotretinoin and alpha interferon in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 1998;21(6):591–4.PubMedCrossRefGoogle Scholar
  78. 78.
    Schefter T, Winter K, Kwon JS, Stuhr K, Balaraj K, Yaremko BP, Small W Jr, Sause W, Gaffney D, Radiation Therapy Oncology Group (RTOG). RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol Biol Phys. 2014;88:101–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Zighelboim I, Wright JD, Gao F, Case AS, Massad LS, Mutch DG, Powell MA, Thaker PH, Eisenhauer EL, Cohn DE, Valea FA, Alvarez Secord A, Lippmann LT, Dehdashti F, Rader JS. Multicenter phase II trial of topotecan, cisplatin and bevacizumab for recurrent or persistent cervical cancer. Gynecol Oncol. 2013;130:64–8.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Bellone S, Frera G, Landolfi G, Romani C, Bandiera E, Tognon G, Roman JJ, Burnett AF, Pecorelli S, Santin AD. Overexpression of epidermal growth factor type-1 receptor (EGF-R1) in cervical cancer: implications for Cetuximab-mediated therapy in recurrent/metastatic disease. Gynecol Oncol. 2007;106(3):513–20.PubMedCrossRefGoogle Scholar
  81. 81.
    Pérez-Regadera J, Sánchez-Muñoz A, De-la-Cruz J, Ballestín C, Lora D, García-Martín R, Mendiola C, Alonso L, Alba E, Lanzós E. Negative prognostic impact of the coexpression of epidermal growth factor receptor and c-erbB-2 in locally advanced cervical cancer. Oncology. 2009;76(2):133–41.PubMedCrossRefGoogle Scholar
  82. 82.
    Farley J, Sill MW, Birrer M, Walker J, Schilder RJ, Thigpen JT, Coleman RL, Miller BE, Rose PG, Lankes HA. Phase II study of cisplatin plus cetuximab in advanced, recurrent, and previously treated cancers of the cervix and evaluation of epidermal growth factor receptor immunohistochemical expression: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;121(2):303–8.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Kurtz JE, Hardy-Bessard AC, Deslandres M, Lavau-Denes S, Largillier R, Roemer-Becuwe C, Weber B, Guillemet C, Paraiso D, Pujade-Lauraine E. Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: a phase II GINECO trial. Gynecol Oncol. 2009;113(1):16–20.PubMedCrossRefGoogle Scholar
  84. 84.
    Cetina L, Crombet T, Jiménez-Lima R, Zapata S, Ramos M, Avila S, Coronel J, Charco E, Bojalil R, Astudillo H, Bazán B, Dueñas-González A. A pilot study of nimotuzumab plus single agent chemotherapy as second- or third-line treatment or more in patients with recurrent, persistent or metastatic cervical cancer. Cancer Biol Ther. 2015;16(5):684–9.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Schilder RJ, Sill MW, Lee YC, Mannel R. A phase II trial of erlotinib in recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Int J Gynecol Cancer. 2009;19(5):929–33.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Goncalves A, Fabbro M, Lhommé C, Gladieff L, Extra JM, Floquet A, Chaigneau L, Carrasco AT, Viens P. A phase II trial to evaluate gefitinib as second- or third-line treatment in patients with recurring locoregionally advanced or metastatic cervical cancer. Gynecol Oncol. 2008;108(1):42–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Candelaria M, Arias-Bonfill D, Chávez-Blanco A, Chanona J, Cantú D, Pérez C, Dueñas-González A. Lack in efficacy for imatinib mesylate as second-line treatment of recurrent or metastatic cervical cancer expressing platelet-derived growth factor receptor alpha. Int J Gynecol Cancer. 2009;19(9):1632–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Monk BJ, Mas Lopez L, Zarba JJ, Oaknin A, Tarpin C, Termrungruanglert W, Alber JA, Ding J, Stutts MW, Pandite LN. 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(22):3562–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Tinker AV, Ellard S, Welch S, Moens F, Allo G, Tsao MS, Squire J, Tu D, Eisenhauer EA, MacKay H. Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). Gynecol Oncol. 2013;130(2):269–74.PubMedCrossRefGoogle Scholar
  90. 90.
    Stevanović S, Draper LM, Langhan MM, Campbell TE, Kwong ML, Wunderlich JR, Dudley ME, Yang JC, Sherry RM, Kammula US, Restifo NP, Rosenberg SA, Hinrichs CS. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells. J Clin Oncol. 2015;33(14):1543–50.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Petit RG, Mehta A, Jain M, Gupta S, Nagarkar R, Kumar V, Premkumar S, Neve R, John S, Basu P. ADXS11-001 immunotherapy targeting HPV-E7: final results from a phase 2 study in Indian women with recurrent cervical cancer. J Immunother Cancer. 2014;2(Suppl 3):P92.PubMedCentralCrossRefPubMedGoogle Scholar
  92. 92.
    Frenel J, Le Tourneau C, O’Neil B, Ott PA, Piha-Paul SA, Gomez-Roca CA, Van Brummelen E, Rugo HS, Thomas S, Saraf S, Chen M, Vargaet A. Pembrolizumab in patients with advanced cervical squamous cell cancer: preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl). abstract 5515.CrossRefGoogle Scholar
  93. 93.
    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(7):1069–74.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    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(2):163–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Santin AD, Sill MW, McMeekin DS, Leitao MM Jr, Brown J, Sutton GP, Van Le L, Griffin P, Boardman CH. Phase II trial of cetuximab in the treatment of persistent or recurrent squamous or non-squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2011;122(3):495–500.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hertlein L, Lenhard M, Kirschenhofer A, Kahlert S, Mayr D, Burges A, Friese K. Cetuximab monotherapy in advanced cervical cancer: a retrospective study with five patients. Arch Gynecol Obstet. 2011;283(1):109–13.PubMedCrossRefGoogle Scholar
  97. 97.
    Lheureux S, Butler M, Clarke B, et al. A phase I/II study of ipilimumab in women with metastatic or recurrent cervical carcinoma: a study of the Princess Margaret and Chicago N01 Consortia. J Clin Oncol. 2015;33(suppl). abstract 3061.Google Scholar
  98. 98.
    Burotto M, Edgerly M, Poruchynsky M, Velarde M, Wilkerson J, Kotz H, Bates S, Balasubramaniam S, Fojo T. Phase II clinical trial of Ixabepilone in metastatic cervical carcinoma. Oncologist. 2015;20(7):725–6.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    MITO (Multicentre Italian Trials in Ovarian cancer): CERV 2 trial “A randomized phase II study of carboplatin and paclitaxel +/- cetuximab, in advanced and/or recurrent cervical cancer. 2015 ASCO Annual Meeting Abstracts Meeting Library; 2016. Available from http://meetinglibrary.asco.org/content/151507-156
  100. 100.
    Longatto-Filho A, Pinheiro C, Martinho O, Moreira MA, Ribeiro LF, Queiroz GS, Schmitt FC, Baltazar F, Reis RM. Molecular characterization of EGFR, PDGFRA and VEGFR2 in cervical adenosquamous carcinoma. BMC Cancer. 2009;9:212.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wang HL, Lu DW. Overexpression of c-kit protein is an infrequent event in small cell carcinomas of the uterine cervix. Mod Pathol. 2004;17(6):732–8.PubMedCrossRefGoogle Scholar
  102. 102.
    Zhang XY, Zhang HY, Zhang PN, Lu X, Sun H. Elevated phosphatidylinositol 3-kinase activation and its clinicopathological significance in cervical cancer. Eur J Obstet Gynecol Reprod Biol. 2008;139(2):237–44.PubMedCrossRefGoogle Scholar
  103. 103.
    Molinolo AA, Marsh C, El Dinali M, Gangane N, Jennison K, Hewitt S, Patel V, Seiwert TY, Gutkind JS. mTOR as a molecular target in HPV-associated oral and cervical squamous carcinomas. Clin Cancer Res. 2012;18(9):2558–68.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Feng W, Duan X, Liu J, Xiao J, Brown RE. Morphoproteomic evidence of constitutively activated and overexpressed mTOR pathway in cervical squamous carcinoma and high grade squamous intraepithelial lesions. Int J Clin Exp Pathol. 2009;2(3):249–60.PubMedGoogle Scholar
  105. 105.
    Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott CL, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Dougherty B, Orr M, Hodgson D, Barrett JC, Matulonis U. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014;15(8):852–61.PubMedCrossRefGoogle Scholar
  106. 106.
    Kunos C, Deng W, Dawson D, Lea JS, Zanotti KM, Gray HJ, Bender DP, Guaglianone PP, Carter JS, Moore KN. A phase I-II evaluation of veliparib (NSC #737664), topotecan, and filgrastim or pegfilgrastim in the treatment of persistent or recurrent carcinoma of the uterine cervix: an NRG Oncology/Gynecologic Oncology Group study. Int J Gynecol Cancer. 2015;25(3):484–92.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    A limited access phase I trial of paclitaxel, cisplatin and ABT-888 in the treatment of advanced, persistent, or recurrent carcinoma of the cervix: an NRG/GOG study. 2015 ASCO Annual Meeting Abstracts Meeting Library; 2015. Available from: http://meetinglibrary.asco.org/content/148460-156
  108. 108.
    Lee SJ, Yang A, Wu TC, Hung CF. Immunotherapy for human papillomavirus- associated disease and cervical cancer: review of clinical and translational research. J Gynecol Oncol. 2016;27:e51.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Mohanty S, Huang J, Basu A. Enhancement of cisplatin sensitivity of cisplatin-resistant human cervical carcinoma cells by bryostatin 1. Clin Cancer Res. 2005;11(18):6730–7.PubMedCrossRefGoogle Scholar
  110. 110.
    Yang W, Song Y, Lu YL, Sun JZ, Wang HW. Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia. Immunology. 2013;139(4):513–22.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Chemoradiation therapy and Ipilimumab in treating patients with locally advanced cervical cancer. ClinicalTrials.gov website. NCT01711515.Google Scholar
  112. 112.
    Nivolumab in Treating patients with persistent, recurrent, or metastatic cervical cancer. ClinicalTrials.gov website. NCT02257528.Google Scholar
  113. 113.
    Falchook GS, Leidner R, Stankevich E, Piening B, Bifulco C, Lowy I, Fury MG. Responses of metastatic basal cell and cutaneous squamous cell carcinomas to anti- PD1 monoclonal antibody REGN2810. J Immunother Cancer. 2016;4:70.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Su X, Chen WJ, Xiao SW, Li XF, Xu G, Pan JJ, Zhang SW. Effect and safety of recombinant Adenovirus-p53 transfer combined with radiotherapy on long-term survival of locally advanced cervical cancer. Hum Gene Ther. 2016;27(12):1008–14.PubMedCrossRefGoogle Scholar
  115. 115.
    Bisht KS, Bradbury CM, Mattson D, Kaushal A, Sowers A, Markovina S, Ortiz KL, Sieck LK, Isaacs JS, Brechbiel MW, Mitchell JB, Neckers LM, Gius D. Geldanamycin and 17- allylamino-17-demethoxygeldanamycin potentiate the in vitro and in vivo radiation response of cervical tumor cells via the heat shock protein 90-mediated intracellular signaling and cytotoxicity. Cancer Res. 2003;63:8984–95.PubMedGoogle Scholar
  116. 116.
    A study of MK1775 in combination with topotecan/cisplatin in patients with cervical cancer (1775–008). ClinicalTrials.gov website. NCT01076400.Google Scholar
  117. 117.
    Wang Y, Decker SJ, Sebolt-Leopold J. Knockdown of Chk1, Wee1 and Myt1 by RNA interference abrogates G2 checkpoint and induces apoptosis. Cancer Biol Ther. 2004;3:305–13.PubMedCrossRefGoogle Scholar
  118. 118.
    Pohlmann P, DiLeone LP, Cancella AI, Caldas AP, Dal Lago L, Campos O Jr, Monego E, Rivoire W, Schwartsmann G. Phase II trial of cisplatin plus decitabine, a new DNA hypomethylating agent, in patients with advanced squamous cell carcinoma of the cervix. Am J Clin Oncol. 2002;25:496–501.PubMedCrossRefGoogle Scholar
  119. 119.
    Feldman R, Gatalica Z, Reddy S, Tewari K. Paving the road to personalized medicine in cervical cancer: Theranostic biomarker evaluation in a 592-specimen library. Gynecol Oncol. 2015;137(Suppl 1):141.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • George Zarkavelis
    • 1
  • Alexandra Papadaki
    • 1
  • Aristides Kefas
    • 2
  • Ioannis Zerdes
    • 1
  • Konstantina Tatsi
    • 3
  • Stergios Boussios
    • 1
  1. 1.Department of Medical OncologyIoannina University HospitalIoanninaGreece
  2. 2.Department of MedicineIoannina University Medical SchoolIoanninaGreece
  3. 3.Gynaecology UnitGeneral Hospital “G. Hatzikosta”IoanninaGreece

Personalised recommendations