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.

Objectives

To assess the effects of all available interventions, surgical and non‐surgical, for the treatment of melanoma in situ, including LM.

Search 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.

Selection criteria

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.

Data collection and analysis

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.

Main 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).

Authors' 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.

Author(s)

Thrasivoulos Tzellos, Athanassios Kyrgidis, Simone Mocellin, An‐Wen Chan, Pierluigi Pilati, Zoe Apalla

Abstract

Plain language summary

Interventions for treatment of melanoma in situ, including lentigo maligna

Background

Melanoma in situ (MIS) is the earliest stage of malignant melanoma. Over the past two decades, the incidence of MIS has increased. Lentigo maligna (LM) is a subtype of pre‐invasive melanoma associated with chronic exposure to ultraviolet radiation, primarily affecting the head and neck. It accounts for 79% to 83% of all MIS tumours. Delayed recognition is common.

Review question

What are the effects of surgical and non‐surgical treatments for MIS, including LM?

Study characteristics

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.

Key results

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.

Quality of the evidence

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.

Author(s)

Thrasivoulos Tzellos, Athanassios Kyrgidis, Simone Mocellin, An‐Wen Chan, Pierluigi Pilati, Zoe Apalla

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

There is a lack of high‐quality evidence for the treatment of melanoma in situ and lentigo maligna. Regarding treatment of melanoma in situ, surgical interventions aiming to optimise margin control (square method, perimeter technique, 'slow Mohs', staged radial sections, staged "mapped" excisions, and Mohs micrographic surgery) are the most widely used interventions recommended as first‐line therapy, although randomised controlled trials of these interventions are missing. The use of non‐surgical interventions in selected cases (patients with contraindications to surgical interventions) may be effective and can be considered preferable for experienced providers and under close and adequate follow up.

Regarding the treatment of lentigo maligna, surgical interventions remain the most widely used and recommended available treatment, although randomised controlled trials are lacking. 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 preferably for experienced providers under close and adequate follow up. The evidence does not support the use of topical therapies, such as 5‐fluorouracil and imiquimod, as neoadjuvant therapy, but 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 the topical inflammatory response and lead to withdrawal of patients due to treatment‐related side‐effects.

Implications for research 

Future studies regarding interventions for the treatment of melanoma in situ and lentigo maligna should be controlled; randomised; and where possible, blinded (particularly the outcome assessor). Adequate follow up to appropriately study important outcomes, such as recurrence rate, is of high importance. When non‐surgical topical interventions, such as imiquimod or retinoids, are compared, an appropriate vehicle can be used to enable blinding, which could lead to a more objective evaluation of these treatments. Future studies should also include a sample size calculation according to a specific clinically relevant outcome, such as complete response (for non‐surgical treatments) and local recurrence rate. Appropriately powered studies are needed. Multicentre studies are greatly needed to both increase sample size and assess variability between centres, especially for surgical interventions.

Since neoadjuvant therapies aim to reduce morbidity, reduce excision margins, and increase treatment‐related quality of life, especially in specific subgroups such as the elderly, it is important that future studies include outcomes such as treatment‐related quality of life and participant satisfaction. Until now, they have been not addressed at all. All future trials should include and assess quality of life outcomes. Future studies must appropriately study and address reduction of excision margins. The use of topical agents, such as 5‐fluorouracil and imiquimod, as neoadjuvant treatments warrant further investigation, especially for outcomes such as reduction of morbidity, decrease of recurrence rate, and reduction of surgical excision margins. It is important that future studies use such outcomes.

Current evidence does not prioritise the need for trials studying the combination of topical retinoid and imiquimod in the treatment of lentigo maligna. Studies of the use of imiquimod as monotherapy in those who are able to undergo surgery are not recommended. Non‐surgical topical interventions as monotherapy can be studied in those who decline surgery or for whom surgical treatment is contraindicated.

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