title: A systematic review on the role of imiquimod in lentigo maligna and lentigo maligna melanoma: need for standardization of treatment schedule and outcome measures.
abstract: Lentigo maligna (LM) is an in situ variant of melanoma. Our objective was to systematically review clinical and histological clearance and recurrence rates of imiquimod treatment of LM with emphasis on progression to lentigo maligna melanoma (LMM). PubMed, EMBASE and the Cochrane library were searched from inception to May 2015. Articles were included if they described histologically proven LM treated with imiquimod 5% monotherapy or combined with another topical therapy. Analysed outcomes were clinical and histological clearance, recurrence rates and number of LMM. The quality was assessed using the GRADE-like checklist, and results were reported according to the PRISMA Statement. Twenty-six case reports, 11 retrospective studies, three prospective studies and one randomized controlled trial were included. One case report of poor quality was excluded. Complete clinical clearance was seen in 369 of 471 patients (78.3%). Histological clearance was present in 285 of 370 (77%) patients. LMM was diagnosed in nine (1.8%) patients 3.9 months (range 0-11 months) post-treatment. Univariate multinominal logistic regression showed that 6-7 applications/week had a 6.47 greater odds (P = 0.017) of resulting in complete clinical clearance compared to 1-4 applications/week. An intensity of 6-7 applications/week showed a 8.85 greater odds (P = 0.003) of resulting in histological clearance compared to 1-4 applications. Applying imiquimod >60 times during a treatment period of 12 weeks (range 4-36) showed a 7.75 greater odds (P = 0.001) of resulting in histological clearance compared to <60 total applications. In conclusion, a treatment schedule using imiquimod 6-7 applications per week, with at least 60 applications, shows the greatest odds of complete clinical and histological clearance of LM. Imiquimod is an option for patients unfit for or not willing to undergo surgery or radiotherapy. Nine cases of LM progressed to LMM shortly after treatment. Our hypothesis is that these LMM may have been present before starting imiquimod.
authors.affiliation: Department of Dermatology, VUmc Amsterdam, Amsterdam, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Tio
authors.affiliation: Flevoziekenhuis Almere, Almere, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van der Woude
authors.affiliation: Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VUmc Amsterdam, Amsterdam, The Netherlands.
authors.forename: C A C
authors.initials: CAC
authors.lastname: Prinsen
authors.affiliation: VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: E P
authors.initials: EP
authors.lastname: Jansma
authors.affiliation: Department of Dermatology, VUmc Amsterdam, Amsterdam, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Hoekzema
authors.affiliation: Department of Dermatology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: van Montfrans
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018450:Disease Progression; D004334:Drug Administration Schedule; D006801:Humans; D018327:Hutchinson's Melanotic Freckle / Q000188:drug therapy* / Q000473:pathology*; D000077271:Imiquimod; D009364:Neoplasm Recurrence, Local; D017063:Outcome Assessment, Health Care / Q000379:methods; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology*
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod