title: Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT³VIN): a multicentre, open-label, randomised, phase 2 trial.
abstract: BACKGROUND
  Vulval intraepithelial neoplasia is a skin disorder affecting the vulva that, if left untreated, can become cancerous. Currently, the standard treatment for patients with vulval intraepithelial neoplasia is surgery, but this approach does not guarantee cure and can be disfiguring, causing physical and psychological problems, particularly in women of reproductive age. We aimed to assess the activity, safety, and feasibility of two topical treatments--cidofovir and imiquimod--as an alternative to surgery in female patients with vulval intraepithelial neoplasia.
  
  
  METHODS
  We recruited female patients (age 16 years or older) from 32 centres to an open-label, randomised, phase 2 trial. Eligibility criteria were biopsy-proven vulval intraepithelial neoplasia grade 3 and at least one lesion that could be measured accurately. We randomly allocated patients to topical treatment with either 1% cidofovir (supplied as a gel in a 10 g tube, to last 6 weeks) or 5% imiquimod (one 250 mg sachet for every application), to be self-applied three times a week for a maximum of 24 weeks. Randomisation (1:1) was done by stratified minimisation via a central computerised system, with stratification by hospital, disease focality, and presentation stage. The primary endpoint was a histologically confirmed complete response at the post-treatment assessment visit 6 weeks after the end of treatment (a maximum of 30 weeks after treatment started). Analysis of the primary endpoint was by intention to treat. Secondary outcomes were toxic effects (to assess safety) and adherence to treatment (to assess feasibility). We present results after all patients had reached the primary endpoint assessment point at 6 weeks; 2-year follow-up of complete responders continues. This trial is registered with Current Controlled Trials, ISRCTN 34420460.
  
  
  RESULTS
  Between Oct 21, 2009, and Jan 11, 2013, 180 participants were enrolled to the study; 89 patients were randomly allocated cidofovir and 91 were assigned imiquimod. At the post-treatment assessment visit, a complete response had been achieved by 41 (46%; 90% CI 37·0-55·3) patients allocated cidofovir and by 42 (46%; 37·2-55·3) patients assigned imiquimod. After 6 weeks of treatment, 156 (87%) patients (78 in each group) had adhered to the treatment regimen. Five patients in the cidofovir group and seven in the imiquimod group either withdrew or were lost to follow-up before the first 6-week safety assessment. Adverse events of grade 3 or higher were reported in 31 (37%) of 84 patients allocated cidofovir and 39 (46%) of 84 patients assigned imiquimod; the most frequent grade 3 and 4 events were pain in the vulva, pruritus, fatigue, and headache.
  
  
  CONCLUSIONS
  Cidofovir and imiquimod were active, safe, and feasible for treatment of vulval intraepithelial neoplasia and warrant further investigation in a phase 3 setting. Both drugs are effective alternatives to surgery for female patients with vulval intraepithelial neoplasia after exclusion of occult invasive disease.
  
  
  BACKGROUND
  Cancer Research UK.
authors.affiliation: HPV Research Group, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Tristram
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Cardiff, UK. Electronic address: hurtcn@cardiff.ac.uk.
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Hurt
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Tracie
authors.initials: T
authors.lastname: Madden
authors.affiliation: HPV Research Group, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Ned
authors.initials: N
authors.lastname: Powell
authors.affiliation: Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Man
authors.affiliation: HPV Research Group, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Hibbitts
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Dutton
authors.affiliation: HPV Research Group, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Sadie
authors.initials: S
authors.lastname: Jones
authors.affiliation: East Kent Gynaecological Oncology Centre, Queen Elizabeth the Queen Mother Hospital, Margate, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Nordin
authors.affiliation: Northern Gynaecological Oncology Centre, Queen Elizabeth Hospital, Gateshead, UK.
authors.forename: Raj
authors.initials: R
authors.lastname: Naik
authors.affiliation: HPV Research Group, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Fiander
authors.affiliation: Wales Cancer Trials Unit, School of Medicine, Cardiff University, Cardiff, UK; University of Southampton Clinical Trials Unit, Faculty of Medicine, Southampton General Hospital, Southampton UK.
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
mesh_terms: D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000473:pathology; D000077404:Cidofovir; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D006801:Humans; D000077271:Imiquimod; D008875:Middle Aged; D060787:Neoplasm Grading; D063065:Organophosphonates / Q000008:administration & dosage* / Q000009:adverse effects; D014846:Vulvar Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000634:Aminoquinolines; D063065:Organophosphonates; D003596:Cytosine; D000077404:Cidofovir; D000077271:Imiquimod