title: Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review.
abstract: BACKGROUND
  Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed.
  
  
  METHODS
  We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease.
  
  
  RESULTS
  Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte-associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer.
  
  
  CONCLUSIONS
  Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy.
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece. Electronic address: stergiosboussios@gmail.com.
authors.forename: Stergios
authors.initials: S
authors.lastname: Boussios
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Seraj
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Zarkavelis
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Petrakis
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: Aristomenes
authors.initials: A
authors.lastname: Kollas
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: Aikaterini
authors.initials: A
authors.lastname: Kafantari
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: Abraam
authors.initials: A
authors.lastname: Assi
authors.affiliation: Gynaecology Unit, General Hospital "G. Hatzikosta", Makrigianni Avenue, 45001, Ioannina, Greece.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Tatsi
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pavlidis
authors.affiliation: Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
mesh_terms: D005260:Female; D006801:Humans; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy; D017671:Platinum Compounds / Q000627:therapeutic use*; D011788:Quality of Life; D012008:Recurrence; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D017671:Platinum Compounds
keywords: Cervix; Chemotherapy; Recurrence; Targeted agents