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Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial

Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial
Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial
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.

Findings: 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.

Interpretation: 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.
1361-1368
Tristram, Amanda
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Hurt, Christopher N.
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Madden, Tracie
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Powell, Ned
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Man, Stephen
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Hibbitts, Sam
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Dutton, Peter
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Jones, Sadie
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Nordin, Andrew J.
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Naik, Raj
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Fiander, Alison
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Griffiths, Gareth
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Tristram, Amanda
9962ca8f-c4d6-476d-bef0-bb9249ccc7f8
Hurt, Christopher N.
36da85a6-401f-4a41-8853-3575c660b365
Madden, Tracie
bb35d5f5-5b05-4673-a408-6e8a8e06af71
Powell, Ned
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Man, Stephen
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Hibbitts, Sam
dc5bb5c9-0925-43e8-85dd-f1f8a0ac3acc
Dutton, Peter
b984314b-813d-41f5-9040-c713c07ebb33
Jones, Sadie
88a38501-176c-4108-96d9-fa359e9efc25
Nordin, Andrew J.
9487167f-58d5-4f06-bb8b-c48af74df76c
Naik, Raj
516f886e-b3ec-4146-895c-701d708e409f
Fiander, Alison
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Griffiths, Gareth
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Tristram, Amanda, Hurt, Christopher N., Madden, Tracie, Powell, Ned, Man, Stephen, Hibbitts, Sam, Dutton, Peter, Jones, Sadie, Nordin, Andrew J., Naik, Raj, Fiander, Alison and Griffiths, Gareth (2014) Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT3VIN): a multicentre, open-label, randomised, phase 2 trial. The Lancet Oncology, 15 (12), 1361-1368. (doi:10.1016/S1470-2045(14)70456-5). (PMID:25304851)

Record type: Article

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.

Findings: 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.

Interpretation: 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.

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More information

e-pub ahead of print date: 7 October 2014
Published date: 7 October 2014
Organisations: Cancer Sciences, Clinical Trials Unit

Identifiers

Local EPrints ID: 370459
URI: http://eprints.soton.ac.uk/id/eprint/370459
PURE UUID: 37944136-d5d9-47f8-aa52-491e9f6872ef
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

Catalogue record

Date deposited: 29 Oct 2014 13:20
Last modified: 15 Mar 2024 03:50

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Contributors

Author: Amanda Tristram
Author: Christopher N. Hurt
Author: Tracie Madden
Author: Ned Powell
Author: Stephen Man
Author: Sam Hibbitts
Author: Peter Dutton
Author: Sadie Jones
Author: Andrew J. Nordin
Author: Raj Naik
Author: Alison Fiander

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