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.

Imiquimod 5% cream in occlusion, for the treatment of lentigo maligna: A new scheme of short cycles and the need for clinical trials

“…Previous retrospective studies have documented a clinical response rate of 73% after a 40-month follow-up (Fosko et al, 2018), while a systematic review of mainly retrospective studies showed a 77% histological clearance rate (Tio et al, 2017).…”

“…Specifically, the better response to imiquimod 5% was present in patients that developed an intense cutaneous reaction with an intense inflammation (Tio et al, 2017). This is due to the mechanism of action of the drug, that is, a Toll-like receptors seven and eight agonist, which allows the release of Interferon-alfa, Tumor Necrosis Factor-alfa and Interleukin-6, increasing the local and systemic immune response.…”

Lymphoedema in patients with lentigo maligna treated with imiquimod: a long-term adverse effect

“…Topical imiquimod is an off‐label option for the treatment of patients with LM who do not qualify for or do not opt for surgical treatment. Imiquimod is applied for a prolonged period of time to achieve a sufficient inflammatory response . We hypothesize that lymphoedema may complicate treatment of patients with LM using topical imiquimod.…”

“…2,3 Complete clinical response rates for LM treated with imiquimod vary from 37Á1% to 100%. [4][5][6] We report three patients with LM who developed lymphoedema following application of topical imiquimod.…”

“…Imiquimod is applied for a prolonged period of time to achieve a sufficient inflammatory response. 5 We hypothesize that lymphoedema may complicate treatment of patients with LM using topical imiquimod. This adverse effect may be caused by the intense treatment regimen used in our patients, resulting in severe inflammation and significant dermal fibrosis, impairing normal tissue drainage by afferent lymphatic vessels.…”