title: Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia.
abstract: BACKGROUND
  Usual-type vulval intraepithelial neoplasia (uVIN) is a pre-cancerous condition of the vulval skin. Also known as high-grade VIN, VIN 2/3 or high-grade vulval squamous intraepithelial lesion (HSIL), uVIN is associated with high-risk subtype human papilloma virus (HPV) infection. The condition causes distressing vulval symptoms in the majority of affected women and may progress to vulval cancer, therefore is usually actively managed. There is no consensus on the optimal management of uVIN. High morbidity and recurrence rates associated with surgical treatments make less invasive treatments highly desirable.
  
  
  OBJECTIVE
  To determine which interventions are the most effective, safe and tolerable for treating women with uVIN.
  
  
  METHODS
  We searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), Issue 8 2015, MEDLINE and EMBASE (up to 1 September 2015). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.
  
  
  METHODS
  Randomised controlled trials (RCTs) that assessed medical and surgical interventions in women with uVIN. If no RCTs were available, we included non-randomised studies (NRSs) with concurrent comparison groups that controlled for baseline case mix in multivariate analysis.
  
  
  METHODS
  We used Cochrane methodology with two review authors independently extracting data and assessing risk of bias. Where possible, we synthesised data in meta-analyses using random-effects methods. Network meta-analysis was not possible due to insufficient data.
  
  
  RESULTS
  We included six RCTs involving 327 women and five NRSs involving 648 women. The condition was variously named by investigators as uVIN, VIN2/3 or high-grade VIN. Five RCTs evaluated medical treatments (imiquimod, cidofovir, indole-3 carbinol), and six studies (one RCT and five NRSs) evaluated surgical treatments or photodynamic therapy. We judged two RCTs and four NRSs to be at a high or unclear risk of bias; we considered the others at relatively low risk of bias. Types of outcome measures reported in NRSs varied and we were unable to pool NRS data. Medical interventions: Topical imiquimod was more effective than placebo in achieving a response (complete or partial) to treatment at five to six months post-randomisation (three RCTs, 104 women; risk ratio (RR) 11.95, 95% confidence interval (CI) 3.21 to 44.51; high-quality evidence). At five to six months, a complete response occurred in 36/62 (58%) and 0/42 (0%) women in the imiquimod and placebo groups, respectively (RR 14.40, 95% CI 2.97 to 69.80). Moderate-quality evidence suggested that the complete response was sustained at one year (one RCT, nine complete responses out of 52 women (38%)) and beyond, particularly in women with smaller VIN lesions. Histologically confirmed complete response rates with imiquimod versus cidofovir at six months were 45% (41/91) and 46% (41/89), respectively (one RCT, 180 women; RR 1.00, 95% CI 0.73 to 1.37; moderate-quality evidence). Twelve-month data from this trial are awaited; however, interim findings suggested that complete responses were sustained at 12 months. Only one trial reported vulval cancer at one year (1/24 and 2/23 in imiquimod and placebo groups, respectively). Adverse events were more common with imiquimod than placebo and dose reductions occurred more frequently in the imiquimod group than in the placebo group (two RCTs, 83 women; RR 7.77, 95% CI 1.61 to 37.36; high-quality evidence). Headache, fatigue and discontinuation were slightly more common with imiquimod than cidofovir (moderate-quality evidence). Quality of life scores reported in one trial (52 women) were not significantly different for imiquimod and placebo. The evidence of effectiveness of topical treatments in immunosuppressed women was scant. There was insufficient evidence on other medical interventions. Surgical and other interventions: Low-quality evidence from the best included NRS indicated, when data were adjusted for confounders, that there was little difference in the risk of VIN recurrence between surgical excision and laser vaporisation. Recurrence occurred in 51% (37/70) of women overall, at a median of 14 months, and was more common in multifocal than unifocal lesions (66% versus 34%). Vulval cancer occurred in 11 women (15.1%) overall at a median of 71.5 months (9 to 259 months). The risk of vulval cancer did not differ significantly between excision and laser vaporisation in any of the NRSs; however, events were too few for robust findings. Alternative surgical procedures that might be as effective include Cavitron ultrasonic surgical aspiration (CUSA) and loop electrosurgical excision (LEEP) procedures, based on low- to very low-quality evidence, respectively. Very low-quality evidence also suggested that photodynamic therapy may be a useful treatment option.We found one ongoing RCT of medical treatment (imiquimod) compared with surgical treatment.
  
  
  CONCLUSIONS
  Topical treatment (imiquimod or cidofovir) may effectively treat about half of uVIN cases after a 16-week course of treatment, but the evidence on whether this effect is sustained is limited. Factors predicting response to treatment are not clear, but small lesions may be more likely to respond. The relative risk of progression to vulval cancer is uncertain. However, imiquimod and cidofovir appear to be relatively well tolerated and may be favoured by some women over primary surgical treatment.There is currently no evidence on how medical treatment compares with surgical treatment. Women who undergo surgical treatment for uVIN have about a 50% chance of the condition recurring one year later, irrespective of whether treatment is by surgical excision or laser vaporisation. Multifocal uVIN lesions are at a higher risk of recurrence and progression, and pose greater therapeutic dilemmas than unifocal lesions. If occult cancer is suspected despite a biopsy diagnosis of uVIN, surgical excision remains the treatment of choice. If occult cancer is not a concern, treatment needs to be individualised to take into account the site and extent of disease, and a woman's preferences. Combined modalities may hold the key to optimal treatment of this complex disease.
authors.affiliation: Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group, Royal United Hospital, Education Centre, Bath, UK, BA1 3NG.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Lawrie
authors.forename: Andy
authors.initials: A
authors.lastname: Nordin
authors.forename: Manas
authors.initials: M
authors.lastname: Chakrabarti
authors.forename: Andrew
authors.initials: A
authors.lastname: Bryant
authors.forename: Sonali
authors.initials: S
authors.lastname: Kaushik
authors.forename: Litha
authors.initials: L
authors.lastname: Pepas
mesh_terms: D000328:Adult; D000634:Aminoquinolines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018450:Disease Progression; D005260:Female; D006801:Humans; D000077271:Imiquimod; D007211:Indoles / Q000627:therapeutic use; D053685:Laser Therapy; D009364:Neoplasm Recurrence, Local; D063065:Organophosphonates / Q000627:therapeutic use; D010778:Photochemotherapy; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D016896:Treatment Outcome; D014846:Vulvar Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D007211:Indoles; D063065:Organophosphonates; D003596:Cytosine; C016517:indole-3-carbinol; D000077404:Cidofovir; D000077271:Imiquimod