title: Interventions for melanoma in situ, including lentigo maligna.
abstract: BACKGROUND
  Malignant melanoma is a form of skin cancer associated with significant mortality once it has spread beyond the skin. Melanoma in situ (MIS) is the earliest histologically recognisable stage of malignant melanoma and represents a precursor of invasive melanoma. Lentigo maligna (LM) represents a subtype of pre-invasive intraepidermal melanoma associated specifically with chronic exposure to ultraviolet (UV) radiation. Over the past two decades, the incidence of MIS has increased significantly, even more than the invasive counterpart. There are several treatment options for MIS, but no consensus exists on the best therapeutic management of this condition.
  
  
  OBJECTIVE
  To assess the effects of all available interventions, surgical and non-surgical, for the treatment of melanoma in situ, including LM.
  
  
  METHODS
  We searched the following databases up to November 2014: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 10), MEDLINE (from 1946), Embase (from 1974), LILACS (from 1982), African Index Medicus (from inception), IndeMED of India (from inception), and Index Medicus for the South-East Asia Region (IMSEAR) (from inception). We scanned the references of included and excluded studies for further references to relevant trials and searched five trials registries. We checked the abstracts of major dermatology and oncology conference proceedings, and we shared our lists of included and excluded studies with industry contacts and other experts in the field of melanoma to try to identify further relevant trials.
  
  
  METHODS
  We included randomised controlled trials (RCT) on the management of MIS, including LM, that compared any intervention to placebo or active treatment. We included individuals, irrespective of age and sex, diagnosed with MIS, including LM, based on histological examination.
  
  
  METHODS
  Two authors independently evaluated possible studies for inclusion; extracted data from the included study using a standard data extraction form modified for our review; assessed risk of bias; and analysed data on efficacy, safety, and tolerability. They resolved any disagreements by discussion with a third author. We collected adverse effects information from included studies.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, Faculty of Health Sciences, University Hospital of North Norway, Harstad, Troms, Norway. ltzellos@googlemail.com. thrasyvoulos.tzellos@unn.no.
authors.forename: Thrasivoulos
authors.initials: T
authors.lastname: Tzellos
authors.forename: Athanassios
authors.initials: A
authors.lastname: Kyrgidis
authors.forename: Simone
authors.initials: S
authors.lastname: Mocellin
authors.forename: An-Wen
authors.initials: AW
authors.lastname: Chan
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Pilati
authors.forename: Zoe
authors.initials: Z
authors.lastname: Apalla
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D006801:Humans; D018327:Hutchinson's Melanotic Freckle / Q000628:therapy*; D000077271:Imiquimod; D008297:Male; D008545:Melanoma / Q000628:therapy*; D009539:Nicotinic Acids / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D012878:Skin Neoplasms / Q000628:therapy*; D000096142:Cutaneous Malignant Melanoma; D012176:Retinoids
chemical_list: D000634:Aminoquinolines; D000970:Antineoplastic Agents; D000077271:Imiquimod; D009539:Nicotinic Acids; C086827:tazarotene; D012176:Retinoids