Topical rapamycin as a treatment for fibrofolliculomas in Birt-Hogg-Dubé syndrome: a double-blind placebo-controlled randomized split-face trial

PLoS One. 2014 Jun 9;9(6):e99071. doi: 10.1371/journal.pone.0099071. eCollection 2014.

Abstract

Background: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder characterised by the occurrence of benign, mostly facial, skin tumours called fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax and an increased renal cancer risk. Current treatments for fibrofolliculomas have high rates of recurrence and carry a risk of complications. It would be desirable to have a treatment that could prevent fibrofolliculomas from growing. Animal models of BHD have previously shown deregulation of mammalian target of rapamycin (mTOR). Topical use of the mTOR inhibitor rapamycin is an effective treatment for the skin tumours (angiofibromas) in tuberous sclerosis complex, which is also characterised by mTOR deregulation. In this study we aimed to determine if topical rapamycin is also an effective treatment for fibrofolliculomas in BHD.

Methods: We performed a double blinded, randomised, facial left-right controlled trial of topical rapamycin 0.1% versus placebo in 19 BHD patients. Trial duration was 6 months. The primary outcome was cosmetic improvement as measured by doctors and patients. Changes in fibrofolliculoma number and size were also measured, as was occurrence of side effects.

Results: No change in cosmetic status of fibrofolliculomas was reported in the majority of cases for the rapamycin treated (79% by doctors, 53% by patients) as well as the placebo treated facial sides (both 74%). No significant differences between rapamycin and placebo treated facial halves were observed (p = 1.000 for doctors opinion, p = 0.344 for patients opinion). No significant difference in fibrofolliculoma number or change in size of the fibrofolliculomas was seen after 6 months. Side effects occurred more often after rapamycin treatment (68% of patients) than after placebo (58% of patients; p = 0.625). A burning sensation, erythema, itching and dryness were most frequently reported.

Conclusions: This study provides no evidence that treatment of fibrofolliculomas with topical rapamycin in BHD results in cosmetic improvement.

Trial registration: ClinicalTrials.gov NCT00928798.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Adult
  • Aged
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / therapeutic use*
  • Birt-Hogg-Dube Syndrome / drug therapy*
  • Birt-Hogg-Dube Syndrome / pathology
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Sirolimus / administration & dosage
  • Sirolimus / adverse effects
  • Sirolimus / therapeutic use*
  • Skin / drug effects*
  • Skin / pathology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / pathology
  • Treatment Outcome

Substances

  • Antibiotics, Antineoplastic
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00928798

Grants and funding

This study was financed by the Myrovlytis Trust (UK Charity Commission number 1122073, http://www.myrovlytistrust.org/). MAMvS and MV are additionally supported by the Dutch Cancer Society, grant UM2009-4352 (http://www.kwfkankerbestrijding.nl). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.