Recurrence of vulval intraepithelial neoplasia following treatment with cidofovir or imiquimod: results from a multicentre, randomised, phase II trial (RT3VIN)

Abstract

ObjectiveTo compare the recurrence rates after complete response to topical treatment with either cidofovir or imiquimod for vulval intraepithelial neoplasia (VIN) 3.DesignA prospective, open, randomised multicentre trial.Setting32 general hospitals located in Wales and England.Population or Sample180 patients were randomised consecutively between 21 October 2009 and 11 January 2013, 89 to cidofoovir (of whom 41 completely responded to treatment) and 91 to imiquimod (of whom 42 completely responded to treatment).MethodsAfter 24 weeks of treatment, complete responders were followed up at 6‐monthly intervals for 24 months. At each visit, the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was assessed and any new lesions were biopsied for histology. Main outcome measuresTime to histologically confirmed disease recurrence (any grade of VIN).ResultsThe median length of follow up was 18.4 months. At 18 months, more participants were VIN‐free in the cidofovir arm: 94% (95% CI 78.2–98.5) versus 71.6% (95% CI 52.0–84.3) [univariable hazard ratio (HR) 3.46, 95% CI 0.95–12.60, P = 0.059; multivariable HR 3.53, 95% CI 0.96–12.98, P = 0.057). The number of grade 2+ events was similar between treatment arms (imiquimod: 24/42 (57%) versus cidofovir: 27/41 (66%), χ2 = 0.665, P = 0.415), with no grade 4+.ConclusionsLong‐term data indicates a trend towards response being maintained for longer following treatment with cidofovir than with imiquimod, with similar low rates of adverse events for each drug. Adverse event rates indicated acceptable safety of both drugsTweetable abstractLong‐term follow up in the RT3VIN trial suggests cidofovir may maintain response for longer than imiquimod.

Refractory extensive vulvar high-grade squamous intraepithelial lesion in an immunosuppressed transplant patient treated with topical cidofovir: A case report

“…At 18-month follow-up after treatment, 94% and 72% of complete responders remained free of disease in cidofovir and imiquimod groups, respectively. 11 Topical cidofovir is usually well tolerated and main side effects include local irritation and ulcerations, which decrease over time. Complete blood count and renal function should be monitored regularly because of the theoretical risk of hematological and renal toxicity described with systemic cidofovir.…”

“…At 18-month follow-up after treatment, 94% and 72% of complete responders remained free of disease in cidofovir and imiquimod groups, respectively. 11…”

A pre‐existing coordinated inflammatory microenvironment is associated with complete response of vulvar high‐grade squamous intraepithelial lesions to different forms of immunotherapy

“…The current standard of care is surgery, which is associated with high comorbidity and recurrence, or topical application of the toll‐like receptor 7 (TLR7) agonist imiquimod to trigger innate immune responses 1,2 . In addition, new approaches are being investigated, aiming at either targeting the virus, using cidofovir, 1 or by strengthening the immune system through systemic therapeutic vaccination to increase T‐cell reactivity against the viral oncoproteins E6 and E7. So far, complete responses have been observed in 35‐46% of patients treated with imiquimod, 1,2 46% of patients treated with cidofovir 1 and 28% of vHSIL patients treated with therapeutic vaccination 3 …”

“…Vulvar high‐grade squamous intraepithelial lesion (vHSIL, previously known as usual vulvar intraepithelial neoplasia, uVIN) is a premalignant lesion predominantly induced by high‐risk human papillomavirus type 16 (HPV16). The current standard of care is surgery, which is associated with high comorbidity and recurrence, or topical application of the toll‐like receptor 7 (TLR7) agonist imiquimod to trigger innate immune responses 1,2 . In addition, new approaches are being investigated, aiming at either targeting the virus, using cidofovir, 1 or by strengthening the immune system through systemic therapeutic vaccination to increase T‐cell reactivity against the viral oncoproteins E6 and E7.…”

“…1,2 In addition, new approaches are being investigated, aiming at either targeting the virus, using cidofovir, 1 or by strengthening the immune system through systemic therapeutic vaccination to increase Tcell reactivity against the viral oncoproteins E6 and E7. So far, complete responses have been observed in 35-46% of patients treated with imiquimod, 1,2 46% of patients treated with cidofovir 1 and 28% of vHSIL patients treated with therapeutic vaccination. 3 Imiquimod is thought to act on macrophages and dendritic cells (DCs), thereby stimulating the local production of pro-inflammatory cytokines such as IFNγ, TNFα and IL-12 which may steer the immune microenvironment towards a milieu that fosters the development of type 1 and cytolytic T-cell responses (reviewed in Reference 4).…”