Abstract: Our search identified only 1 study eligible for inclusion (and 1 ongoing study in active recruitment stage), which was a single centre, open label, parallel group, 2-arm RCT with 90 participants, who had 91 histologically proven LM lesions. Forty-four participants, with 44 LM lesions, were treated with imiquimod 5% cream 5 days per week plus tazarotene 0.1% gel 2 days/week for 3 months, and 46 participants, with 47 LM lesions, were treated with imiquimod 5% cream 5 days per week for 3 months. Two months after cessation of topical treatment, the initial tumour footprint was excised using 2 mm margins via a staged excision. This study was open label, and analysis was not intention-to-treat, leading to a high risk of incomplete outcome data. Our primary outcome 'Histological or clinical complete response' was measured at 5 months in 29/44 participants (66%) treated with imiquimod plus tazarotene (combination therapy) and 27/46 participants (59%) treated with imiquimod (monotherapy). The difference was not statistically significant (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.81 to 1.55, P value = 0.48). With regard to our secondary outcomes on recurrence and inflammation, after a mean follow up of 42 months, no local recurrences were observed among complete responders. Difference in overall inflammation score between the 2 groups was significant (mean difference (MD) 0.6, 95% CI 0.2 to 1, P value = 0.004), with the mean overall inflammation score being significantly higher in the combination group. The study authors did not clearly report on side-effects. Because of adverse effects, there was a dropout rate of 6/44 participants (13.7%) in the combination group compared with 1/46 (2.2%) in the imiquimod monotherapy group (due to excessive inflammation) before the cessation of topical treatment (first 3 months), but this was not statistically significant (RR 6.27, 95% CI 0.79 to 50.02, P value = 0.08). There is a lack of high-quality evidence for the treatment of MIS and LM. For the treatment of MIS, we found no RCTs of surgical interventions aiming to optimise margin control (square method, perimeter technique, 'slow Mohs', staged radial sections, staged "mapped" excisions, or Mohs micrographic surgery), which are the most widely used interventions recommended as first-line therapy. The use of non-surgical interventions in selected cases (patients with contraindications to surgical interventions) may be effective and may be considered preferable for experienced providers and under close and adequate follow up. For the treatment of LM, we found no RCTs of surgical interventions, which remain the most widely used and recommended available treatment. The use of non-surgical interventions, such as imiquimod, as monotherapy may be effective and may be considered in selected cases where surgical procedures are contraindicated and used preferentially by experienced providers under close and adequate follow up. The use of topical therapies, such as 5-fluorouracil and imiquimod, as neoadjuvant therapies warrants further investigation. There is insufficient evidence to support or refute the addition of tazarotene to imiquimod as adjuvant therapy; the current evidence suggests that it can increase topical inflammatory response and withdrawal of participants because of treatment-related side-effects.

Plain-language summary: We identified one randomised controlled clinical trial (RCT) of the non-surgical treatment of 90 people with LM: 44 were treated with imiquimod cream plus tazarotene gel, and 46 were treated with imiquimod cream for 3 months; these interventions were followed by staged excision after 2 months. We did not find any RCTs of surgical treatments. Of those treated with imiquimod and tazarotene, 66% had a complete response at 5 months compared with 59% of those treated with imiquimod alone. The addition of tazarotene to imiquimod did not lead to a clinically better response, and the people in this group had higher inflammation. There were more dropouts due to adverse effects in this group. The quality of evidence is poor. With regard to the treatment of MIS, surgical interventions that aim to excise the tumour so that none of the tumour cells are in the margin are the most recommended interventions in non-selected cases. The evidence does not support the use of non-surgical interventions in selected cases (i.e., in elderly people with contraindications to surgical interventions). However, clinical centres may consider it where there is experience of this treatment and where close and adequate follow up can be undertaken. With regard to the treatment of LM, surgical interventions remain the most recommended available treatment. The evidence does not support the use of non-surgical interventions, such as imiquimod, as a single therapy in non-selected cases. It may be considered only in selected cases and in clinical centres with experience. The evidence so far does not support the use of imiquimod as a neoadjuvant (i.e., before surgery) therapy but warrants further investigation, in order to evaluate if use after surgery can minimise recurrence and if use before surgery of large lesions or difficult sites can help to achieve smaller surgical excisions. The evidence does not support addition of tazarotene to imiquimod as neoadjuvant therapy.