Interventions for melanoma in situ, including lentigo maligna.

Interventions for melanoma in situ, including lentigo maligna (Review) Tzellos T, Kyrgidis A, Mocellin S, Chan AW, Pilati P, Apalla Z

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 12 http://www.thecochranelibrary.com

Interventions for melanoma in situ, including lentigo maligna (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 1 Primary outcome: Histological complete response (ITT). . . . . . . . . . . . Analysis 1.2. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 2 Primary outcome: Histological complete response (available-case analysis). . . . . . Analysis 1.3. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 3 Secondary outcome: Discontinuation of treatment because of harms. . . . . . . . Analysis 1.4. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants. Analysis 1.6. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3). . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


1 1 2 4 6 9 9 12 14 16 19 21 21 22 26 30 30 31 31

32 32 33 33 34 36 36 37 37 38

i

[Intervention Review]

Interventions for melanoma in situ, including lentigo maligna Thrasivoulos Tzellos1 , Athanassios Kyrgidis2,3,4 , Simone Mocellin5 , An-Wen Chan6 , Pierluigi Pilati5 , Zoe Apalla7 1 Department

of Dermatology, Faculty of Health Sciences, University Hospital of North Norway, Harstad, Norway. 2 Division of Evidence Based Dermatology, Dessau Medical Center, Dessau, Germany. 3 Dermatology and Skin Cancer Unit, Arcispedale Santa Maria Nuova, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Reggio Emilia, Italy. 4 1st Department of Otolaryngology, Head & Neck Surgery, Aristotle University of Thessaloniki, Thessaloniki, Greece. 5 Meta-Analysis Unit, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy. 6 Women’s College Research Institute, University of Toronto, Toronto, Canada. 7 State Clinic of Dermatology, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece Contact address: Thrasivoulos Tzellos, Department of Dermatology, Faculty of Health Sciences, University Hospital of North Norway, Harstad, Troms, Norway. [email protected]. [email protected]. Editorial group: Cochrane Skin Group. Publication status and date: New, published in Issue 12, 2014. Review content assessed as up-to-date: 26 November 2014. Citation: Tzellos T, Kyrgidis A, Mocellin S, Chan AW, Pilati P, Apalla Z. Interventions for melanoma in situ, including lentigo maligna. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD010308. DOI: 10.1002/14651858.CD010308.pub2. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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. Interventions for melanoma in situ, including lentigo maligna (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

1

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.

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? Interventions for melanoma in situ, including lentigo maligna (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2

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.


3


S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Imiquimod 5% cream with tazarotene 0.1% gel compared with Imiquimod 5% cream alone for melanoma in situ, including lentigo maligna Patient or population: participants with melanoma in situ, including lentigo maligna Settings: 1 academic centre in the US Intervention: imiquimod 5% cream with tazarotene 0.1% gel Comparison: imiquimod 5% cream alone Outcomes

Illustrative comparative risks* (95% CI)

Assumed risk

Relative effect (95% CI)

Number of participants (studies)

Quality of the evidence (GRADE)

Comments

Corresponding risk

Imiquimod 5% cream Imiquimod 5% cream alone with tazarotene 0.1% gel Primary outcome: 587 per 1000 Histological complete response (intention-totreat) No residual LM in staged excision 2 months posttreatment

657 per 1000 (475 to 910)

RR 1.12 (0.81 to 1.55)

90 (1 study)

⊕⊕

low¹

-

Primary outcome: 659 per 1000 Histological complete response ( availablecase analysis) No residual LM in staged excision 2 months posttreatment

784 per 1000 (593 to 1000)

RR 1.19 (0.9 to 1.57)

78 (1 study)

⊕⊕

low¹

-

Secondary outcome: 22 per 1000 Discontinuation of treatment because of harms Discontinuation of treatment due to adverse ef-

136 per 1000 (17 to 1000)

RR 6.27 (0.79 to 50.02)

90 (1 study)

⊕⊕

low¹

-

4


fects Secondary outcome: 591 per 1000 Inflammatory response (number of lesions with grade 2 or 3) Grade 2 or 3 Inflammation²

815 per 1000 (615 to 1000)

RR 1.38 (1.04 to 1.84)

Secondary outcome: Inflammatory response (overall Inflammation score) for all participants Mean grade of inflammation in each group²

The mean overall inflammation score (inflammatory response) for all participants in the intervention groups was 0.60 higher (0.2 to 1 higher)

88 (1 study)

⊕⊕

low¹

-

88 (1 study)

⊕⊕

low¹

-

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio. GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate. GRADE = Grading of Recommendations Assessment, Development and Evaluation. LM = lentigo maligna. ¹Published evidence is limited to a single randomised trial. ²(0 indicates no inflammation; 1, pink; 2, red; and 3, the presence of erosions, oozing, or eschar).

5

BACKGROUND Please note that we have listed unfamiliar terms in Table 1.

Description of the condition Melanoma is one of the deadliest types of skin neoplasm (abnormal growth), resulting from the uncontrollable proliferation of malignant melanocytes (cells within the epidermis) (Bichakjian 2011). Melanoma in situ (MIS) is the earliest histologically recognisable stage of malignant melanoma, and it is characterised by an increased number of atypical intraepidermal melanocytes (King 2005; Tannous 2000). The disease is clinically relevant because it represents a precursor of invasive melanoma. Individuals diagnosed with melanoma in situ have a higher risk of developing invasive melanoma in their lifetime (Mocellin 2011). Over the past two decades, the incidence of melanoma in situ has increased significantly, even more than the invasive counterpart (Charles 2005), which has led some authors to state that we are witnessing a kind of melanoma epidemic (Beddingfield 2003; Mocellin 2011). Lentigo maligna (LM) represents a subtype of pre-invasive intraepidermal melanoma associated specifically with chronic exposure to ultraviolet (UV) radiation, primarily affecting the head and neck region. It is the most prevalent melanoma in situ subtype, accounting for 79% to 83% of all melanoma in situ tumours (Kvaskoff 2011; McKenna 2006). Lentigo maligna melanoma (LMM) represents 4% to 15% of all melanomas (Clark 1986; McKenna 2006; McLeod 2011). Its incidence is increasing in people older than 45 years, at a greater rate than for any other melanoma subtype (Swetter 2005). Swetter et al report that regional (California) and national data suggest an increasing incidence of LM and LMM, particularly in men above 65 years of age (Swetter 2005). Furthermore, in a recently published population-based study held in the US, investigators report that the incidence of LM increased significantly among residents of Olmsted County, Minnesota, over a 37-year period, with incidence being significantly higher among men than women and increasing with age (Mirzoyev 2014). Across 21 years of incidence data for in situ and invasive lesions from the population-based Queensland Cancer Registry in Australia, MIS increased by 10.4% per year among males and 8.4% per year among females. The incidence of invasive lesions also increased, but not as quickly (Coory 2006). In a study evaluating incidence trends, age incidence relationships, and familial risks in invasive and in situ cutaneous melanoma, investigators in Sweden recorded a marked increase in incidence of MIS, particularly after 1985. Among MIS, lentigo maligna was the most common histogenetic type, almost three times more common than superficially spreading melanoma. The study obtained data from the Swedish Cancer Registry for the years 1961 to 1998 (Hemminki 2003).

The real risk of progression from LM to LMM is not known; Cohen has widely reviewed this and estimated the risk to be “as high as 30% to 50% or as low as 5% based on epidemiologic data” (Cohen 1995). Taking into account that observational, longitudinal, or prospective studies in people with LM are not feasible (since they would require no treatment), the precise lifetime risk of invasive melanoma in this group remains unknown. Investigators have estimated a lifetime risk essentially based on anecdotal experience. There is only one epidemiologic study that has aimed to establish the annual and lifetime risk of malignant transformation of LM (Weinstock 1987). Based on their records, the investigators reported that a person with LM at the age of 45 would have a 3.3% risk of LMM by the age of 75 and a lifetime risk of 4.7% (Weinstock 1987). Diagnosis of LM at the age of 65 was associated with a 1.2% risk of LMM by the age of 75 and a 2.2% lifetime risk (Weinstock 1987). The treatment of MIS, particularly the LM subtype, has been a controversial subject in the literature for over a decade. In the optimal scenario of being able to distinguish LM from LMM clinically, or being able to predict the risk of progression, close monitoring would be a reasonable alternative to treatment. However, since such a scenario is currently impossible, active treatment of LM is recommended (Bichakjian 2011). These considerations have drawn special attention to the treatment of LM (Erickson 2010).

Clinical characteristics and diagnosis Presentation of melanoma in situ may be quite subtle, and delayed recognition is common. Diagnosis is based on clinical, dermoscopic, and histological features. In terms of clinical presentation, it usually develops as an ill-defined, darkly pigmented flat lesion, with irregular borders and a diameter larger than 0.7 cm. With regard to LM, the presence of widespread atypical melanocytes in the background of long-standing sun damage are highly indicative of the disease (Brochez 2002; Farmer 1996; Koehler 2011; Megahed 2002). However, differentiation from lentigo senilis, initial seborrhoeic keratosis, or pigmented actinic keratoses may be difficult (Cognetta 2001). The four most important diagnostic features for LM or LMM on dermoscopy are “asymmetric pigmented follicular openings, dark rhomboidal structures, slate-gray globules, and slate-gray dots with a sensitivity of 89% and a specificity of 96%” (Schiffner 2000).

Description of the intervention Many interventions, including both surgical and non-surgical therapeutic approaches, are used for the management of melanoma in situ. Surgical excision, including Mohs microsurgery, remains the gold standard therapeutic practice for people with melanoma in situ (Clark 2008; Cohen 1998; Dawn 2007; Kunishige 2011; Mahoney 2005; Osborne 2002).


6

Surgical excision

1. Regular excision with 5 mm margins

With regard to surgery, in 1992, the National Institutes of Health (NIH) consensus statement established surgical excision with 5 mm clinical margins as the standard treatment for melanoma in situ (National Institutes of Health 1993). However, taking into consideration cumulative evidence from multiple studies over recent years, the conclusion has been made that 5 mm margins are often insufficient to histologically clear the LM variant (National Comprehensive Cancer Network 2009). The National Comprehensive Cancer Network’s (NCCN) Guidelines of Care for Melanoma discussed the possible need for > 5 mm margins in larger melanoma lesions of the lentigo maligna subtype (National Comprehensive Cancer Network 2009); these guidelines stated that more extensive histological assessment of the margins may need to be considered in such cases. Thus, the conclusion from these guidelines and Stevenson 2005, who showed that high rates of recurrence following standard excisional surgery, attributed to subclinical extension, is that a 5 mm surgical margin for excision of melanoma in situ is often insufficient for the LM subtype. In this context, given the need for extended margins, alternative techniques aiming to optimise margin control have been employed, including the square method, perimeter technique, ’slow Mohs’, staged radial sections, staged “mapped” excisions, and Mohs micrographic surgery (MMS) (Clark 2008).

2. The square method

When using the square method, after drawing the original margins of the lesion, a new margin in the shape of a square or polygon is drawn at a distance of 5 mm from the original 1. Then, an additional square is drawn 2 to 3 mm around the latter polygon. This 2 to 3 mm slide of tissue around the lesion is excised, leaving behind a thin frame-like defect that is simply sutured closed while waiting for the histopathologic report of the excised tissue. If the report is positive, another square frame is excised from the periphery, and the process is repeated until clear margins are obtained. At the final stage, the central part is excised, and the individual undergoes a reconstruction. “The key advantages of the ’square’ method are that it allows the use of high-quality permanent sections for total peripheral margin assessment and it avoids creating an open wound for the patient to care for while awaiting closure” (Clark 2008). One big disadvantage is that the individual must wait some time for pathology reports, possibly resulting in delayed complete excision. This important disadvantage of the square method has resulted in adaptations of the surgical technique (Clark 2008; Jejurikar 2007; Johnson 1997). For example, the central part of the tumour is removed at first visit, without performing reconstruction (Agarwal-Antal 2002; Clark 2008; Mahoney 2005). This modification facilitates

“staging prior to reconstruction but creates an open wound. Another common modification is the use of specific polygons [or curved lines] instead of a true square” (Clark 2008). “This allows the surgeon to match the surgical defect with the shape of the melanoma in situ as well as the surrounding cosmetic units and structures” (Clark 2008). Furthermore, straight lines are retained to facilitate histological processing. “Finally, another common modification is the use of 24-hour rush permanent sections instead of routine processing” (Bub 2004). 3. The “mapped” excision method

Hill and Gramp first described “mapped” excision in 1999 (Hill 1999), as well as the ’radial processing’ described by Bub, et al (Bub 2004). “While often included in review articles of melanoma in situ treatment for completeness, these forms of staged excisions do not employ en face [parallel to the surgical margins] histological processing and represent fundamentally different modalities than either the square method and its modifications or Mohs micrographic surgery” (Clark 2008). 4. Mohs micrographic surgery

Mohs micrographic surgery (MMS) is a surgical and pathological procedure used to treat many cutaneous neoplasms (Clark 2008; Mohs 1941). “Its design integrates the role of surgeon and pathologist and is unique in providing assessment of 100% of surgical margins intraoperatively, in contrast to a significantly lower percentage of assessed margins, typically 0.1% (Zitelli 1997) to 5%, by standard specimen analysis” (Shriner 1998). “Mohs micrographic surgery has the advantage of offering intraoperative margin control with assessment of 100% of margins, and it does not require a separate dermatopathologist to be available for rush specimen analysis” (Clark 2008). Even though the overall process may take several hours, achieving definitive excision and closure on the same day is a big advantage of MMS. A drawback of MMS is “the difficulty associated with adequately preparing frozen sections for [visualisation] of melanocytes, including the need for immunohistochemical stains” (Clark 2008). However, besides the progress in the field of excision techniques, the question concerning the initial margin size needed to clear a clinically ill-defined tumour still remains (Erickson 2010). Non-surgical interventions Localisation of lesions in cosmetically sensitive sites, such as the head and neck area, often raise serious difficulties for surgeons, who aim for complete clearance of the tumour, while seeking to minimise morbidity to the area. Similarly, the difficulty of obtaining wide excision margins in some body areas, together with the higher prevalence of lentigo maligna in the elderly (who may have contraindications to surgical procedures), has led to investigation of other less invasive treatment methods (Erickson 2010). In this


7

context, radiotherapy (Farshad 2002; Tsang 1994); cryosurgery (Collins 1991); laser surgery (Kopera 1995); and topical medication have been used with variable success, especially for individuals with large patches of LM, or those who are not otherwise good candidates for surgery (Rajpar 2006; Ray 2005; Rodriguez Prieto 1993; Ryan 1988). Apart from their use as primary treatments, non-surgical techniques can contribute as adjuvant therapies after surgical excision, in order to minimise recurrence, or after incomplete excision to further enhance the therapeutic response. A recent trend also includes application of non-ablative treatments as neoadjuvant therapies, before surgical treatment of large lesions or difficult sites, in order to achieve smaller surgical excisions (Gupta 2004), although there is concern over the potential for creating non-contiguous tumour islands.

Cryosurgery Cryosurgery has been proposed as an alternative to surgical excision for lentigo maligna (Field 1995). It is recommended in people for whom surgery is not appropriate. The cryosurgery technique varies. Kufiick and Gage suggested “aggressive treatment [using] double freeze-thaw cycles with a 1 cm margin and temperatures of -40 to -50°C at the base of the lesion” (Kuflik 1994). A significant drawback in cryosurgery is the lack of a histological evaluation of the destroyed specimen. As a result of the latter, no assessment of microscopic foci of lentigo maligna melanoma or identification of aggressive melanoma subtypes can be made. On the same basis, it does not give any clue to the prognostic outcome based on histological grade in case of an invasive tumour. Imiquimod

Lasers Carbon dioxide laser ablation, Q-switched neodymium-doped yttrium aluminium garnet (QS Nd:YAG), and alexandrite lasers have all been used in the treatment of LM in those elderly people who may be unsuitable for surgery (Lee 2011; Madan 2009).

Curettage and electrodesiccation Curettage and electrosurgery have been used for the treatment of lentigo maligna (Coleman 1980). Usually, a looped metal instrument (curettage) is used to ’scrape’ the lesion’s surface and remove part or the whole of the lesion, and an electric current (electrosurgery) is applied to cauterise and destroy an area of the lesion. Recurrences have been observed. The main drawback of this technique is the lack of histological analysis. It has also been reported that atypical melanocytes in the hair follicle are not likely to be destroyed using this technique (Gaspar 1997).

Radiation therapy “Radiation therapy is [a] non-invasive treatment modality that has been used as a primary treatment for lentigo maligna. It is appealing in elderly patients who may be poor surgical candidates and in patients with large lentigo malignas on the face that would require a large surgical excision” (Garbe 2008). Cure rates for lentigo maligna achieved with radiotherapy, with either Grenz rays or soft X-rays using the Miescher technique, range from 86% to 95% (Farshad 2002; Schmid-Wendtner 2000; Tsang 1994). The German Cancer Society suggested “radiotherapy as a potential second line treatment for lentigo maligna in their 2008 guidelines (Garbe 2008). The [therapeutic] protocol reported in these guidelines includes Grenz ray therapy (12 kV) for LM (100 to 120 Gy; 10 Gy twice weekly for 5 to 6 weeks). However, the German consensus statement did conclude that radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable”.

Imiquimod belongs to the synthetic imidazoquinoline amine family. It is used as a topical immune-response modifier, and is officially approved for the treatment of superficial basal cell carcinoma, actinic keratoses, and external genital warts. Because of the antitumour effect of imiquimod, it has been used for many other neoplasias, including melanoma in situ (Ray 2005). However, success rates are variable, and recurrence with progression to invasive melanoma has been reported (Woodmansee 2009). Azelaic acid Azelaic acid has been successfully used in the treatment of lentigo maligna melanoma (Rodriguez Prieto 1993; Vereecken 2002). The precise mechanism of action responsible for this beneficial effect remains obscure. Numerous investigators have used azelaic acid 20% in a cream, or 15% to 55% in ointment, for a number of months to over a year for the treatment of lentigo maligna (Rodriguez Prieto 1993; Vereecken 2002). However, the results have varied between studies. 5-fluorouracil Topical chemotherapy of lentigo maligna of the face with 5-fluorouracil 5% cream has been used (Litwin 1975).

How the intervention might work Of the main interventions mentioned above, cryosurgery acts through the direct ’killing’ of the melanocytes at temperatures of - 4 to -7 °C (Gage 1979), and imiquimod activates the innate immune response by binding to receptors on neutrophils, macrophages, and dendritic cells. This leads to synthesis and release of cytokines, including tumour necrosis factor-α (Kang 2009), which has been shown to have significant antitumour effects. There have been several studies of the mechanism of action of azelaic acid (Addo-Boadu 1996; Leibl 1985), but “inhibition of DNA synthesis is one of the mechanisms by which azelaic acid prevents growth


8

and proliferation of abnormal melanocytes” (Leibl 1985). Finally, 5-fluorouracil inhibits a cell’s ability to synthesise DNA by inducing cell cycle arrest and apoptosis (programmed cell death) (Desai 2012).

Types of outcome measures

Why it is important to do this review

Primary outcomes

We think it is very important to systematically evaluate all of the available surgical and non-surgical therapeutic options for the treatment of melanoma in situ, since it predisposes to the deadliest type of skin cancer (i.e., invasive melanoma), and its incidence is growing rapidly. We published the plans for this review as a protocol ’Interventions for melanoma in situ, including lentigo maligna’ (Apalla 2013).

OBJECTIVES To assess the effects of all available interventions, surgical and nonsurgical, for the treatment of melanoma in situ, including LM. We also aimed to assess efficacy, harms, and tolerability of postoperative adjuvant therapies after surgical treatment, as well as the efficacy, harms, and tolerability of non-surgical interventions preoperatively (neoadjuvant therapies), in order to facilitate surgical removal.

METHODS

Criteria for considering studies for this review Types of studies We included randomised controlled trials of any design of the management of melanoma in situ, including LM, that compared any intervention to placebo or active treatment.

The outcome measures of interest were those that estimated clinical efficacy, harms, or tolerability in a reliable and valid way.

1. Histological or clinical complete response rate. 2. Total number of acute and short-term (up to one year) treatment-related adverse events.

Secondary outcomes

1. Clinical or histological local recurrence rate. 2. Time to complete histological or clinical clearance (for surgical and non-surgical treatments). 3. Time to histological or clinical local recurrence. 4. Incidence of distal metastases. 5. Progression to invasive melanoma. 6. Short-, medium-, and long-term participant satisfaction. 7. Treatment-related quality of life. 8. Discontinuation of treatment rate because of harms. 9. Inflammatory response.

Main outcomes for the ’Summary of findings’ table

We provided data in the Summary of findings for the main comparison for the primary and secondary outcomes.

Timing of outcomes

We summarised and pooled outcomes according to the following time schedule: up to one year, between one to five years, and longer than five years from treatment initiation, for the short-, medium, and long-term outcomes, respectively. We classified treatmentrelated harms as ’acute’ if they arose during treatment or within two weeks of treatment completion. Analysis of participant satisfaction took place at the same time points.

Types of participants We included individuals, irrespective of age and sex, diagnosed with melanoma in situ, including LM, based on histological examination by healthcare practitioners.

Economic data

We did not consider economic factors in this review.

Types of interventions We included surgical (regular excision with 5 mm margins, Mohs surgery, staged excision, etc.) and non-surgical (imiquimod, lasers, cryosurgery, etc.) treatments, alone or in combination with other treatments, for the management of melanoma in situ, including LM.

Search methods for identification of studies We aimed to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).


9

Electronic searches We searched the following databases up to 26 November 2014: • the Cochrane Skin Group Specialised Register using the search strategy in Appendix 1; • the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2014, Issue 10) using the strategy in Appendix 2; • MEDLINE via Ovid (from 1946) using the strategy in Appendix 3; • Embase via Ovid (from 1974) using the strategy in Appendix 4; and • LILACS (Latin American and Caribbean Health Science Information database, from 1982) using the strategy in Appendix 5. We searched the following databases up to 30 November 2014 using the strategy in Appendix 6: • African Index Medicus (indexmedicus.afro.who.int, from inception); • IndMED of India (indmed.nic.in, from inception); and • Index Medicus for the South-East Asia Region (IMSEAR) (from inception).

further relevant trials on melanoma in situ and also whether they were aware of melanoma trials where a subset of participants had melanoma in situ. Conference proceedings

In order to identify eligible studies from conference proceedings, we checked the Conference Proceedings Citation Index, accessed via Web of Science™ Core Collection, and Cochrane conference proceedings up to 17 February 2014. We scanned the abstracts of the following major dermatology and oncology conference proceedings, where they were not already recorded in the Cochrane Skin Group Specialised Register: • American Academy of Dermatology (2008/2009); • European Academy of Dermatology and Venereology (EADV) (from 2006); • European Academy of Dermatology and Venereology Spring Symposium (from 2006); • Society for Investigative Dermatology (SID) (2007/2008/ 2009); and • World Congress of Dermatology (from 2002). Adverse effects

Trials registers

We searched the following trials registers up to 30 November 2014 using the following search string: [“lentigo maligna” OR “lentigo maligna melanoma” OR “Hutchinson Melanotic Freckle” OR “melanoma in-situ” OR “melanoma in situ” OR “melanomain-situ” OR (melanoma NEAR in-situ)]. • The metaRegister of Controlled Trials (www.controlledtrials.com). • The US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov). • The Australian New Zealand Clinical Trials Registry ( www.anzctr.org.au). • The World Health Organization International Clinical Trials Registry platform (who.int/trialsearch). • The South African National Clinical Trials Register ( www.sanctr.gov.za). Searching other resources

References from published studies

We checked the bibliographies of included and excluded studies for further references to relevant trials. Unpublished literature

We tried to identify further relevant trials by sharing our lists of included and excluded studies with industry contacts and other experts in the field of melanoma. We asked if they knew of any

We did not perform a separate search for adverse effects of the target interventions. We considered adverse effects and side-effects described in included studies only.

Data collection and analysis Some parts of the methods section of this review uses text that was originally published in theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Selection of studies Two authors (TT and AK) independently examined titles and abstracts of each reference identified in the search results. We checked them independently and resolved any differences related to what we should include or exclude by referring to a third author (SM or AWC). We obtained the full text of all articles that either met the inclusion criteria or for which reading the full text was necessary to decide on their eligibility. Data extraction and management Two review authors (TT and AK) independently extracted the data on to a standard data extraction form, which we had modified for our review. Although we were blinded to each other’s data extraction, we were not blinded to the journal of publication or to the trial author names. We resolved differences by discussion with a third author (SM or AWC). We extracted data according to Table 7.3.a ’Checklist of items to consider in data collection or


10

data extraction’ in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Two review authors (TT and AK) entered data into the ’Characteristics of included studies’ table in Review Manager 2014 (RevMan). Briefly, we tried to extract the following data: general study information, trial methodology, key variables characterising the participants, key variables characterising the lesion, key variables characterising the intervention, outcomes, and results. • General study information ◦ Author ◦ Publication status (full report/abstract/unpublished data) ◦ ◦ ◦ ◦ ◦ ◦

Year of trial initiation Publication date Source of study/funding Setting (place trial was conducted) Dual publication Language of original publication

• Trial methodology ◦ ◦ ◦ ◦ ◦ ◦ ◦

Design Type of trial Study duration Sequence generation Allocation sequence concealment Participant/provider and outcome assessor blinding Number of participants allocated to each treatment

group ◦ Number of dropouts and reasons for dropouts ◦ Intention-to-treat analysis or not ◦ Method/duration of follow-up period • Key variables characterising the participants ◦ Age ◦ Sex ◦ Nationality ◦ Duration of lesion ◦ Comparability of study groups at entry ◦ Inclusion and exclusion criteria ◦ Recruitment method ◦ Number of participants enrolled ◦ Previous treatment ◦ Immunocompetent or not (e.g., B-cell lymphoma, transplantation) • Key variables characterising the lesion ◦ ◦ ◦ ◦

Type of lesion Site Size How the diagnosis was established (histological criteria

used) ◦ Melanotic or amelanotic

◦ One or multiple lesions ◦ Type of biopsy used (punch, excisional, incisional) • Key variables characterising the intervention ◦ Type of intervention ⋄ For surgical intervention: type of surgical procedure (standard excision, Mohs surgery, etc.), size of postoperative surgical defect, number of stages required; type of reconstruction ⋄ For topical treatment: duration, mode of application, time of application, if occlusion or not, when treatment stopped (e.g., weeping erosion appeared), if concomitant treatment (cryotherapy) applied, if inflammatory response appeared ◦ Use of concomitant therapy ◦ Evidence of compliance monitoring ◦ For cryotherapy: mode of application, description of freeze-thaw cycles ◦ For laser: type of laser (Argon, Q-switched ruby, QS Nd:YAG, alexandrite laser), method of application • Outcomes ◦ Outcomes used and time points ◦ Diagnostic criteria used and outcome definition • Results ◦ Lost to follow up ◦ Summary data for each intervention group ◦ Mean and standard deviation for continuous data ◦ The number of participants with the outcome event and the denominator for categorical outcomes ◦ Estimate of effect with confidence intervals ◦ Subgroup analyses (specific subsets of participants) Assessment of risk of bias in included studies Two review authors (TT and AK) independently assessed the quality and the risk of bias of the eligible study. We resolved any disagreement by discussion and arbitration or by consensus with a third author (SM or AWC). Where necessary, we contacted trial authors for clarification. Quality evaluation and assessment of the risk of bias included evaluation of the following components for the included trial, using the ’Risk of bias’ tool suggested in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011): (a) method of generation of the randomisation sequence; (b) method of allocation concealment - we considered this as adequate if the assignment could not be foreseen by either participants or investigator; (c) blinding (who was blinded/not blinded) in order to assess performance bias - we considered this adequate if participants, investigators, and assessors were blinded as to who received the intervention and who received the placebo/other treatment;


11

(d) loss to follow up (in each arm); and (e) whether participants were analysed in the groups to which they were originally randomised (intention-to-treat). Furthermore, we assessed if baseline comparisons of groups regarding important confounding variables were made, in order to assess selection bias. We also carefully assessed the following: 1. if method and duration of follow-up period were adequate; 2. definition of partial clearance; 3. definition of complete clinical clearance; and 4. definition of clinical local recurrence.

would have ascertained that significant heterogeneity was present. Thus, we would have explored this using prespecified subgroup analyses taking into consideration reasons, such as differences in participants and treatment factors.

Measures of treatment effect

Data synthesis

We expressed dichotomous outcomes as risk ratios (RR), with 95% confidence intervals (CIs). We expressed continuous outcomes as mean differences (MD), with 95% CIs. We expressed continuous outcomes that were measured with different methodologies across studies as standardised mean differences (SMD), with 95% CIs.

If there had been sufficient studies and if no evidence of heterogeneity between eligible studies existed (I² statistic < 25%), we aimed to synthesise data using fixed-effect models. Otherwise, we would have used random-effects models. For dichotomous outcomes, we would have pooled risk ratios (RR) and corresponding 95% confidence intervals (CI) from individual studies. For continuous outcomes, we would have pooled the mean difference (MD) and corresponding 95% CIs from individual studies.

Unit of analysis issues If we had found cross-over trials, we would have only considered data from the first period. We would have pooled data from the first period of cross-over trials with data from parallel-group studies. If multiple-treatment group trials were eligible, we would have combined groups to create a single pair-wise comparison following recommendations from the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 16) (Higgins 2011). If there were no relevant intervention groups that we could combine, we would have considered multiple-treatment meta-analyses. For intraindividual studies, we would have considered each body part as the unit of analysis. Dealing with missing data We analysed the data in our included trial as if the analysis was undertaken using intention-to-treat. If the analysis of the trial data had been performed using per-protocol analysis or it was clear that the number of participants analysed for the outcome were not the same as those randomised, thereby excluding intention-totreat analysis, we would have contacted the original investigators to obtain missing data. If contact with the author was not fruitful, we would have used imputation techniques, if possible, based on assumptions - the validity of which we would have assessed through sensitivity analyses. If the results of the sensitivity analysis were suggestive of bias, we would have performed available-case analysis and reported (with the intention of comparing the two) the results of both methods.

Assessment of reporting biases If we had included more than 10 studies in the meta-analysis, we had planned to use funnel plots to visually analyse the existence of publication bias. Additionally, we aimed to perform the Egger’s test (Egger 1997) to formally assess the symmetry of funnel plots.

Subgroup analysis and investigation of heterogeneity Following assessment of heterogeneity, we aimed to perform exploratory subgroup analysis to identify factors that could explain efficacy, safety, or tolerability, or that could explain heterogeneity. The following were possible subgroups. • Study factors ◦ Design ◦ Risk of bias of included studies ◦ Length of follow up • Treatment factors ◦ Length of treatment ◦ Treatment schedule The number of studies included was insufficient, and we were not able to consider these factors. Sensitivity analysis We had planned to perform sensitivity analyses to examine the effects of excluding study subgroups or certain studies of low methodological quality.

RESULTS Assessment of heterogeneity We would have assessed statistical heterogeneity using I² statistic. If I² statistic for the primary outcomes was greater than 50%, we

Description of studies


12

We report the characteristics of studies in the ’Characteristics of included studies’ table, ’Characteristics of excluded studies’ tables, and ’Characteristics of ongoing studies’ table. A summary of findings is presented in Summary of findings for the main comparison. Results of the search Figure 1 depicts a study flow diagram. In summary, we identified 809 records in total. We removed 27 duplicates, leaving 782 records for screening. Following exclusion of 774 records on the

basis of title and abstract, we screened 8 for eligibility and inclusion with full text assessment. From these 8 studies, we excluded 4 and provided reasons in the ’Characteristics of excluded studies’ tables; we cannot currently make a decision about 2 studies, so they are detailed in the ’Characteristics of studies awaiting classification’ tables; 1 other study is ongoing in the active recruitment phase and fulfilled the criteria for inclusion (NCT01720407). One study, Hyde 2012, was completed with results and fulfilled criteria for inclusion.


13

Figure 1. Study flow diagram


14

Included studies Our search identified only one study eligible for inclusion, Hyde 2012, with 90 participants.

Design

This was a randomised, single centre, open label, parallel group, two-arm, controlled trial.

Participants

Ninety participants (24 women, 66 men), who had 91 lentigo maligna (LM) lesions with histologically proven LM, participated and underwent initial shave excision of any visible tumour. The mean age of the participants was 68.2 years (age range: 35 to 92).

Interventions

Forty-four participants (13 women, 31 men), with 44 LM lesions, were treated with imiquimod 5% cream 5 days/week (from Monday to Friday) plus tazarotene 0.1% gel 2 days/week (Saturday and Sunday) for 3 months, and 46 participants (11 women, 35 men), with 47 LM lesions, were treated with imiquimod 5% cream 5 days/week (from Monday to Friday) for 3 months. Participants in all groups treated an area extending 1 inch (2.54 cm) beyond the outlined tumour margins. Two months after cessation of topical treatment, the initial tumour footprint was excised using 2 mm margins via a staged excision with radial frozen sections and melan-A immunostaining to confirm negative margins.

Outcomes

The primary outcome of the study was histological complete response (histological complete clearance) at month five after the initiation of treatment. The secondary outcomes included local recurrence rate, progression to invasive melanoma, discontinuation of treatment because of harms, and overall inflammation score (inflammatory response).

Excluded studies We excluded four studies and provide reasons for their exclusion in the ’Characteristics of excluded studies’ tables. After evaluation of the full text, we found that two did not include people with melanoma in situ (Khayat 2003; Kim 2008), and two did not compare treatments (Chagpar 2007; Morganroth 2009). Studies awaiting classification Two studies that were randomised controlled trials were unclear if they included participants with melanoma in situ (Amatetti 1994; Foster 2007). One of these studies compared efficacy of horizontal Mohs tissue processing to vertical breadloaf tissue processing in the surgical management of superficial melanoma (Foster 2007), and the other studied adjuvant therapy with recombinant alphainterferon in non-metastatic melanoma (Amatetti 1994). We contacted the contact authors of these studies in order to obtain more information, but they did not respond to our request. We have included them in the studies awaiting classification section and provide their known characteristics in the ’Characteristics of studies awaiting classification’ tables. Therefore, we were unable to include them in the current systematic review. Ongoing studies Our search identified one ongoing study (NCT01720407), of which we provide details in the ’Characteristics of ongoing studies’ table. This is a randomised, parallel group, two-arm, open label trial in active recruitment status. The aim of this study is to assess the relevance of imiquimod as neoadjuvant treatment to reduce excision size and the risk of intralesional excision in LM of the face. This study includes participants with LM of the face or neck, histologically confirmed by biopsy. Group A is treated with imiquimod (5 times per week) applied to and extending 1 cm beyond the lesion for a period of 4 weeks, and group B, with vehicle (5 times per week) applied to and extending 1 cm beyond the lesion for a period of 4 weeks. In both groups, surgery performed four weeks after the last application of the topical treatment follows local treatment. The primary outcome of this study is margin of resection. An at least 5 mm healthy tissue margin beyond lesion periphery defines successful resection with proper margins. This study started on October 2012, and MEDA Pharma GmbH & Co. KG sponsors it.

Setting

Only one centre in a university-setting participated in this study. The study had no funding support. Contact with the corresponding author of the included study (Dr Mark Hyde) was successful, and he provided access to primary study data and replied, when possible, to all of our inquiries.

Risk of bias in included studies We categorised judgements in order to indicate a low, high, or unclear risk of bias. The ’Risk of bias’ graph (Figure 2) summarises the results, in addition to the ’Risk of bias’ table within the ’ Characteristics of included studies’ table.


15

Figure 2. ’Risk of bias’ summary: review authors’ judgements about each ’Risk of bias’ item for each included study

Allocation

Randomisation We deemed the risk of selection bias from the random sequence generation as low; this is because the study used a 1:1 random number table for 2 interventions generated by the clinical trials office at the institution.

Allocation We initially judged the risk of selection bias from allocation concealment as unclear since authors did not report on this. However, contact with the study authors clarified that the study used a centralised service, so we deemed the risk of selection bias from allocation concealment as low. Blinding


16

We judged the risk of bias as high since this was an open label trial and study participants, medical staff, and study staff were not blinded after the assignment was made. The study authors reported that blinding was not possible because of the nature of the study. However, a vehicle (placebo) treatment could have been used instead of tazarotene in the group that received imiquimod monotherapy. Further, blinded outcome assessment is usually possible for pathologists and clinical assessors.

made phone calls and asked them if they had seen another dermatologist or asked them to look at the scar and tell them if they saw any pigment in or around the scar. Unfortunately, Dr Hyde did not have records to tell us how many came back to clinic and how many follow-ups were completed by phone. We therefore judged the risk of bias regarding method of follow up after the initial five months as high and deemed the method insufficient.

Definition of local recurrence

Incomplete outcome data We judged the risk of bias as high because 5/46 participants from the imiquimod-alone group and 7/44 participants from the imiquimod-tazarotene group withdrew consent or dropped out because of adverse effects. The study partially provided reasons. The study did not report intention-to-treat analysis.

We judged the risk of bias regarding definition of local recurrence as high. The study authors did not report the definition of local recurrence. The corresponding author of the study, Dr Hyde, was unable to provide any further information.

Effects of interventions

Other potential sources of bias

See: Summary of findings for the main comparison Imiquimod 5% cream with tazarotene 0.1% gel compared with Imiquimod 5% cream alone for melanoma in situ, including lentigo maligna We provided data in the Summary of findings for the main comparison for the primary and secondary outcomes. Imiquimod 5% cream with tazarotene 0.1% gel is the ’combination’ therapy and is compared with imiquimod 5% cream alone, which is referred to as the ’monotherapy’.

Definition of incomplete response

Primary outcomes

Selective reporting We judged the risk of bias as low since the study reported all prespecified outcomes. The corresponding author of the study, Dr Hyde, provided us with all the data needed to evaluate it.

We judged the risk of bias as low since the study clearly reported definition of incomplete response, which we deemed sufficient. 1. Histological or clinical complete response rate Similarity of groups at baseline

We judged the risk of bias as unclear. Although we deemed the randomisation process sufficient and correct, the study authors did not present important baseline characteristics of the two groups, such as size of lesions, which could be potential confounding variables.

Method and duration of follow up

We judged the risk of bias regarding duration of follow-up period as low as we deemed the follow-up period adequate (mean was 42 months). We judged the risk of bias regarding method of follow up for the initial five months as low as we deemed the method of follow up for this time period sufficient. The original article did not report the method of follow up after the initial five months (after surgery). The corresponding author of the study, Dr Mark Hyde, kindly provided additional data about this. He reported that follow up was done in clinic where possible. For those participants who did not come back to clinic, researchers

This outcome was measured at five months, which fits our classification of short-term (up to one year). The study authors reported that in the imiquimod monotherapy group, 27 out of 41 (65%) participants who reached the end point of the study had complete histological response. In the combination group (imiquimod with tazarotene), 29 out of 37 participants (78%) who reached the intended treatment duration had complete histological response. We contacted the corresponding author to obtain information regarding the participants who dropped out, and he kindly gave us access to primary data. We employed intention-to-treat analysis, characterising all participants who dropped out as treatment failures or not complete responders. We decided to do so taking into account the nature of the disease under investigation. Twenty-nine out of 44 participants (66%) treated with imiquimod and tazarotene and 27 out of 46 participants (59%) treated with imiquimod monotherapy had complete clearance at 5 months. The difference was not statistically significant (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.81 to 1.55, P value = 0.48; Analysis 1.1). We also employed analysis only for the participants who finished the study, as it had been reported by the study authors. Results did


17

not show a statistically significant difference between groups (combination therapy versus monotherapy). The complete response RR (risk ratio) was 1.19 (95% CI 0.90 to 1.57, P value = 0.22; Analysis 1.2). We carefully analysed the primary data that Dr Hyde provided. Of the five participants who dropped out from the imiquimod monotherapy group, three never started the treatment and withdrew consent. The other two started the topical treatment but did not finish it. These last two participants had complete response after subsequent surgery. From the seven participants who dropped out of the combination group, four had complete response; for one participant, data were missing; and the other two did not have a complete response. After evaluation of the data and taking into account the nature of the disease, we decided not to impute these data in any analysis. Because we identified only one study with a modest number of participants, we graded the quality of the evidence as low. See Summary of findings for the main comparison.

3. Time to histological or clinical local recurrence

The study did not measure or report this outcome. 4. Incidence of distal metastases

The study did not assess or report Incidence of distal metastases. 5. Progression to invasive melanoma

One participant out of the 44 participants from the combination-therapy group (imiquimod plus tazarotene) developed invasive melanoma (0.32 Breslow depth and Clark level III) at the treatment site in the 2-month interval between topical therapy completion and surgery. This fits our classification of short-term (up to one year). The imiquimod monotherapy group reported no cases of invasive melanoma. 6. Short-, medium-, and long-term participant satisfaction

The study did not measure or report this outcome. 2. Total number of acute and short-term (up to one year) treatment-related adverse events

The protocol of Hyde 2012 did not include overall treatmentrelated adverse events from non-surgical or surgical interventions, but it did include total inflammation score (inflammatory response) (see below: Secondary outcome 9: Inflammatory response). Although this outcome can be considered as a treatmentrelated adverse event, it is also an outcome that has been suggested to be associated with the efficacy of local treatment with imiquimod.

Secondary outcomes

1. Clinical or histological local recurrence rate

The study did not report any recurrences in the mean follow-up period of 42 months. This fits with our classification of mediumterm (from year one up to year five). The study authors reported that prior to initiation of topical treatment (in order to avoid the risk of treating invasive lentigo maligna melanoma (LMM)) with topical imiquimod, all visible signs of LM were removed using a shave excision at the first visit. The corresponding author of the study informed us that there were eight people who had died of unrelated causes during this follow-up period. Of those who dropped out of the study, follow-up data were available for only one person.

2. Time to complete histological or clinical clearance (for surgical and non-surgical treatments)

The study did not measure or report this outcome.

7. Treatment-related quality of life

The study did not measure or report this outcome. 8. Discontinuation of treatment because of harms

One participant out of 46 (2.2%) in the imiquimod monotherapy group dropped out due to excessive inflammation (inflammation grade of 3) before the cessation of topical treatment (first 3 months). Six out of 44 participants (13.7%) dropped out due to adverse events before the cessation of topical treatment (first 3 months). The result of the comparison was not statistically significant (RR 6.27, 95% CI 0.79 to 50.02, P value = 0.08; Analysis 1.3). As this single study was insufficiently powered to document a real difference between the two groups, we graded the quality of the evidence as low. See Summary of findings for the main comparison. 9. Inflammatory response

The study graded inflammatory response by the maximum intensity observed using a scale of zero to three (none: no inflammation; one: pink; two: red; three: presence of erosions, oozing, or eschar). The study authors reported that participants in the combination therapy group had a significantly higher overall inflammation score (mean = 2.3) than those in the monotherapy group (mean = 1.8). These values correspond to the participants who reached the end point of the trial. The study authors did not report on the participants who dropped out; however, we contacted them and obtained primary data for all participants. We first analysed the primary data of the participants who completed the study. Mean overall inflammation score for the


18

monotherapy group was 1.738 and standard deviation was 0.989 (41 participants). Mean overall inflammation score for the combination group was 2.297 and standard deviation was 0.9 (37 participants). Difference in overall inflammation score between the 2 groups was significant (mean difference (MD) 0.56, 95% CI 0.14 to 0.98, P value = 0.009; Analysis 1.4). Mean overall inflammation score was significantly higher in the combination group compared to the monotherapy group. We also analysed all data for all participants regarding the inflammatory response. For three participants from the imiquimod monotherapy group, no topical treatment was initiated and no data recorded. We decided to exclude these three participants from the analysis. For the other 43 participants, we imputed the highest grade of inflammation recorded per case. Mean inflammation score was 1.7 and standard deviation was 1 in the monotherapy group (43 participants). Regarding the 44 participants from the combination group, we imputed the highest grade of inflammation recorded per case. Mean inflammation score was 2.3, and standard deviation was 0.93 (44 participants). Difference in overall inflammation score between the 2 groups was statistically significant (MD 0.6, 95% CI 0.2 to 1, P value = 0.004; Analysis 1.5). Mean overall inflammation score was significantly higher in the combination group compared with the monotherapy group. Given that for one of the groups the mean score (2.29) is close to the maximum (3), these methods that are suitable for normally distributed data might under- or over-estimate the mean difference (Higgins 2011). Because we had contacted the study authors and the original data values were available, we re-analysed the inflammation scores using non-parametric methods suitable for ordinal data (Mann-Whitney U test). Mann-Whitney U test - using ranks - yielded an identical P value (P value = 0.004), with the mean difference method supported by Review Manager (Review Manager 2014). Even though this difference is most probably real, because we identified only one study with a modest number of participants, we graded the quality of the evidence as low. See Summary of findings for the main comparison. We conducted a posthoc analysis regarding the number of lesions that achieved a grade two or three inflammatory response. Analysis of all primary data indicated that 26 of the 44 lesions in the monotherapy group achieved a grade 2 or 3 inflammatory response. In the combined therapy group, 36 of 44 lesions achieved a grade 2 or 3 inflammatory response. The difference between the 2 groups was statistically significant in favour of monotherapy (RR 1.38, 95% CI 1.04 to 1.84, P value = 0.02; Analysis 1.6). As we only identified one study with a modest number of participants, we graded the quality of the evidence as low. See Summary of findings for the main comparison.

DISCUSSION

Summary of main results This systematic review tried to summarise all available interventions for the treatment of melanoma in situ, including lentigo maligna. We identified only one randomised, single centre, open label, parallel group, two-arm, controlled trial. The trial treated 44 participants with imiquimod 5% cream plus tazarotene 0.1% gel (combination therapy group) and 46 participants with Imiquimod 5% cream (monotherapy group). Regarding our primary outcome ’Histological or clinical complete response rate’, there was no statistically significant difference (RR 1.12, 95% CI 0.81 to 1.55, P value = 0.48, intention-to-treat (ITT) analysis) between the combination (66%) and monotherapy groups (59%). The best complete response rate was 78% for the combination group and 66% for the monotherapy group. With regard to our secondary outcomes, discontinuation of treatment because of harms was not statistically significant. Inflammatory response was reported as mean inflammatory score; this is an interesting outcome that is a treatment-related adverse event. However, it has also been suggested that it could be an outcome related to efficacy of imiquimod. Mean overall inflammation score was statistically significantly higher in the combination group. Interestingly, although combination therapy exhibited a significantly higher degree of inflammation, this did not translate to a significant increase in the completed histological response rate. This suggests that the quantity of inflammation may not be a factor associated with increased efficacy. Enhancing drug penetration with tazarotene did not increase the complete response rate but did lead to substantially more inflammation. One person out of the 44 participants from the combination therapy group developed invasive melanoma. This emphasises the need for close, adequate, and structured follow up at predefined periods for people treated with imiquimod as monotherapy. In the mean follow-up period of 42 months, the study reported no local recurrences. Previously published recurrence rates for stage excision alone are approximately 6% (Bub 2004; Lee 2008; Walling 2007). Whether or not addition of imiquimod as neoadjuvant treatment can decrease local recurrence rate remains a question that future studies should properly address.

Overall completeness and applicability of evidence This systematic review identified only one study eligible for inclusion and one ongoing study. It is unlikely that the results of the only included study can facilitate clinicians in making evidencebased treatment decisions. Important outcomes for the evaluation of imiquimod as neoadjuvant treatment, such as reduction of excision size, morbidity, and quality of life, are not properly addressed, although these may be important clinically relevant outcomes. There is insufficient evidence to support or refute the addition of tazarotene to imiquimod as adjuvant therapy. Since tazarotene


19

is one of the strongest topical retinoids (with only isotretinoin 0.05% gel being stronger), addition of any other retinoid is not recommended and is likely to highly increase inflammation and dropout of patients from treatment with no significant efficacy gain.

Quality of the evidence There is a paucity of randomised controlled trials (RCTs) and high-quality evidence for the treatment of melanoma in situ and lentigo maligna. Appropriate studies of the most important clinically relevant outcomes, such as recurrence rate; reduction of excision size with the use of neoadjuvant treatments; morbidity; and participant-rated outcomes, such as satisfaction rate and quality of life, are needed. Our included study was a single centre, open label, parallel group trial with only 90 participants allocated in 2 arms, thus, not adequately powered; no sample size calculation according to any specific clinically relevant outcome was made. The comparisons of interventions in the study were relevant to this disease, but do not cover the range of outcomes this review is aimed at. We downgraded all the outcomes we examined by two levels to reflect the fact that the single eligible study by Hyde 2012 was subject to a high risk of bias due to lack of blinding, partially incomplete outcome data, and method of follow up. Overall, we judged the evidence to be of low quality, meaning that future studies will modify confidence in the estimate of effect, which in turn could be reversed.

Potential biases in the review process We assessed risk of bias as low for random sequence generation and selective reporting, definition of incomplete response, and duration of follow up. There was no blinding of participants, personnel, or outcome assessors; therefore, we judged blinding as at high risk of bias. Analysis was not intention-to-treat, leading to a high risk of incomplete outcome data. We deemed method of follow up after the initial five months and definition of local recurrence as at high risk of bias. These parameters are of high significance. The study did not report information on similarity of groups at baseline for important confounding variables such as the size of the lesion. We need to mention several limitations of this systematic review. “As with any [review] there is the potential for publication bias to over-estimate differences in outcomes if studies identifying such differences are more likely to be published in peer-reviewed journals” (Sladden 2009). This review has the limitation of solely depending on a single study to detect real differences in outcomes. The total number of participants recruited in the included study was not based on a sample size calculation, and the study was insufficiently powered to rule out clinically relevant differences.

We made a substantial effort to obtain information on studies that might include a subset of people with melanoma in situ or lentigo maligna melanoma (LMM). We identified two studies that might be eligible for inclusion in this review, but it was unclear if they included participants with melanoma in situ or LMM (Amatetti 1994; Foster 2007), so this makes our review somewhat incomplete. We contacted the study authors to obtain further information, but to date, they have not responded, so we have detailed these in the ’Characteristics of studies awaiting classification’ tables.

Agreements and disagreements with other studies or reviews One systematic review, Fogarty 2014, tried to summarise the published evidence for the use of radiotherapy in the treatment of LM, focusing on technical aspects in order to develop the best evidence-based radiotherapy protocol. The authors included any type of studies and could identify only retrospective case series. They concluded that there is a lack of standardisation of the studies, and overall, they could not identify the optimum parameters for radiotherapy. A review of treatments for LM tried to comprehensively review available evidence (McLeod 2011). The authors employed a specific search strategy with prespecified key search terms, which did not have any restrictions regarding the type of studies, and they included all investigational studies of any design, both prospective and retrospective. They found a number of studies: 12 examining staged surgical excision, 9 using Mohs micrographic surgery, 6 investigating cryosurgery, 22 investigating imiquimod, 7 using lasers, 9 investigating radiation therapy, and 2 investigating electrosurgery and curettage. The authors presented tables with important outcomes and variables. They concluded that staged surgical excision and Mohs micrographic surgery are linked with the lowest recurrence rates for LM and that cryotherapy and radiation therapy may be contemplated as the options for treatment of LM in people who cannot endure surgery (McLeod 2011). They also suggested that imiquimod may have a future role to play in the treatment of LM. Another review summarised the treatment options specifically for melanoma in situ (Erickson 2010). The authors employed a specific search strategy that did not restrict the types of studies included and presented tables for many important variables. They concluded that “topical imiquimod therapy appears to provide relatively low cure rates” and should be used with extreme caution. “Radiation therapy may be a useful second-line therapy if surgery is contraindicated”. They clearly suggest that “excisional surgery is an appropriate therapy for clinically well-defined melanomas in situ. However, margins larger than 5 mm may be required when treating larger or indistinct lesions.” We excluded from this systematic review all of the studies (except one) included in the aforementioned reviews because they were


20

case series, retrospective, and uncontrolled studies. These types of studies were not eligible for inclusion in this systematic review, since we restricted the predefined inclusion criteria to randomised controlled trials. Our review and all of the aforementioned three reviews reported limited evidence.

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 5fluorouracil 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.

ACKNOWLEDGEMENTS We wish to thank Dr Mark Hyde, corresponding author of the included study (Hyde 2012), for replying to our requests and providing access to primary data of the study. We would also like to thank Shaheen Haque Hussain, co-author of the protocol (Apalla 2013), who withdrew her name from the author list of the review. The Cochrane Skin Group editorial base wishes to thank Sam Gibbs, who was the Cochrane Dermatology Editor for this review; Matthew Grainge and Thomas Chu, who were the Statistical Editors; Ching-Chi Chi, who was Methods Editor; the clinical referees, Susan O’Connell and Eleni Linos; and the consumer referee, Colette O’Sullivan.


21

REFERENCES

References to studies included in this review Hyde 2012 {published and unpublished data} Hyde MA, Hadley ML, Tristani-Firouzi P, Goldgar D, Bowen GM. A Randomized Trial of the Off-Label Use of Imiquimod, 5%, Cream with vs without Tazarotene, 0.1%, Gel for the Treatment of Lentigo Maligna, Followed by Conservative Staged Excisions. Archives of Dermatology 2012;148(5):592–6. [MEDLINE: 22431716]

References to studies excluded from this review Chagpar 2007 {published data only} Chagpar RB, Ross MI, Reintgen DS, Edwards MJ, Scoggins CR, Martin RC, et al.Factors associated with improved survival among young adult melanoma patients despite a greater incidence of sentinel lymph node metastasis. Journal of Surgical Research 2007;143(1):164–8. [MEDLINE: 17950088] Khayat 2003 {published data only} Khayat D, Rixe O, Martin G, Soubrane C, Banzet M, Bazex JA, et al.Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick): Long-term results of a large European multicentric phase III study. Cancer 2003;97(8):1941–6. [EMBASE: 2003143819] Kim 2008 {published data only} Kim KB, Eton O, Davis DW, Frazier ML, McConkey DJ, Diwan AH, et al.Phase II trial of imatinib mesylate in patients with metastatic melanoma. British Journal of Cancer 2008;99(5):734–40. [EMBASE: 2008407391] Morganroth 2009 {published data only} Morganroth PA, Gelfand JM, Jambusaria A, Margolis DJ, Miller CJ. A randomized, double-blind comparison of the total dose of 1.0% lidocaine with 1:100,000 epinephrine versus 0.5% lidocaine with 1:200,000 epinephrine required for effective local anesthesia during Mohs micrographic surgery for skin cancers. Journal of the American Academy of Dermatology 2009;60(3):444–52. [EMBASE: 2009076713]

References to studies awaiting assessment

Dermatology 2007;56(2 Suppl 2):AB145. [DOI: 10.1016/ j.jaad.2006.10.672]

References to ongoing studies NCT01720407 {unpublished data only} NCT01720407. Relevance of Imiquimod as Neoadjuvant Treatment to Reduce Excision Size and the Risk of Intralesional Excision in Lentigo Malignant of the Face (ImiReduc). clinicaltrials.gov/show/NCT01720407 (accessed 20 March 2014).

Additional references Addo-Boadu 1996 Addo-Boadu K, Wojta J, Christ G, Hufnagl P, Pehamberger H, Binder BR. Azelaic acid decreases the fibrinolytic potential of cultured human melanoma cells in vitro. Cancer Letters 1996;103(2):125–9. [MEDLINE: 8635147] Agarwal-Antal 2002 Agarwal-Antal N, Bowen GM, Gerwels JW. Histologic evaluation of lentigo maligna with permanent sections: implications regarding current guidelines. Journal of American Academy of Dermatology 2002;47(5):743–8. [MEDLINE: 12399768] Beddingfield 2003 Beddingfield FC. The melanoma epidemic: res ipsa loquitur. Oncologist 2003;8(5):459–65. [MEDLINE: 14530499] Bichakjian 2011 Bichakjian CK, Halpern AC, Johnson TM, Foote Hood A, Grichnik JM, Swetter SM, et al. Guidelines of care for the management of primary cutaneous melanoma. American Academy of Dermatology. Journal of American Academy of Dermatology 2011;65(5):1032–47. [MEDLINE: 21868127] Brochez 2002 Brochez L, Verhaeghe E, Grosshans E, Haneke E, Piérard G, Ruiter D, et al.Inter-observer variation in the histopathological diagnosis of clinically suspicious pigmented skin lesions. Journal of Pathology 2002;196(4): 459–66. [MEDLINE: 11920743]

Amatetti 1994 {published data only} Amatetti M, Proietto G, Paolini A, Feliciani C, Cazzato C, Amerio P. Adjuvant therapy with recombinant alpha-interferon in non metastatic melanoma [TERAPIA ADIUVANTE CON INTERFERON–ALFA RICOMBINANTE NEL MELANOMA CUTANEO]. Giornale Italiano di Dermatologia e Venereologia 1994;129 (6):31–6. [EMBASE: 1994345755]

Bub 2004 Bub JL, Berg D, Slee A, Odland PB. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year follow-up. Archives of Dermatology 2004; 140(5):552–8. [MEDLINE: 15148099]

Foster 2007 {published data only} Foster W, Esser A, Monheit G, Harmon C. A Prospective Randomized Study Comparing the Efficacy of Horizontal Mohs Tissue Processing to Vertical Breadloaf Tissue Processing in the Surgical Management of Superficial Melanoma. Journal of the American Academy of

Charles 2005 Charles CA, Yee VS, Dusza SW, Marghoob AA, Oliveria SA, Kopf A, et al.Variation in the diagnosis, treatment, and management of melanoma in situ: a survey of US dermatologists. Archives of Dermatology 2005;141(6): 723–9. [MEDLINE: 15967918]


22

Clark 1986 Clark WH, Elder DE, Van Horn M. The biologic forms of malignant melanoma. Human Pathology 1986;17(5): 443–50. [MEDLINE: 3699806] Clark 2008 Clark GS, Pappas-Politis EC, Cherpelis BS, Messina JL, Möller MG, Cruse CW, et al.Surgical management of melanoma in situ on chronically sun damaged skin. Cancer Control 2008;15(3):216–24. [MEDLINE: 18596673] Cognetta 2001 Cognetta AB, Stolz W, Katz B, Tullos J, Gossain S. Dermatoscopy of lentigo maligna. Dermatologic Clinics 2001;19(2):307–18. [MEDLINE: 11556239] Cohen 1995 Cohen LM. Lentigo maligna and lentigo maligna melanoma. Journal of American Academy of Dermatology 1995;33(6):923–36. [MEDLINE: 7490362] Cohen 1998 Cohen LM, McCall MW, Zax RH. Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. A follow-up study. Dermatologic Surgery 1998;24(6):673–7. [MEDLINE: 9648576] Coleman 1980 Coleman WP, Davis RS, Reed RJ, Krementz ET. Treatment of lentigo maligna and lentigo maligna melanoma. Journal of Dermatologic Surgery & Oncology 1980;6(6):476–9. [MEDLINE: 7391322] Collins 1991 Collins P, Rogers S, Goggin M, Manning W. Cryotherapy for lentigo maligna. Clinical & Experimental Dermatology 1991;16(6):433–5. Coory 2006 Coory M, Baade P, Aitken J, Smithers M, McLeod GR, Ring I. Trends for in situ and invasive melanoma in Queensland, Australia, 1982-2002. Cancer Causes & Control 2006;17(1): 21–7. [MEDLINE: 16411049] Dawn 2007 Dawn ME, Dawn AG, Miller SJ. Mohs surgery for the treatment of melanoma in situ: a review. Dermatologic Surgery 2007;33(4):395–402. [MEDLINE: 17430372] Desai 2012 Desai T, Chen CL, Desai A, Kirby W. Basic pharmacology of topical imiquimod, 5-fluorouracil, and diclofenac for the dermatologic surgeon. Dermatological Surgery 2012;38(1): 97–103. [PUBMED: 22092926] Egger 1997 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629–34. [MEDLINE: 9310563] Erickson 2010 Erickson C, Miller SJ. Treatment options in melanoma in situ: topical and radiation therapy, excision and Mohs surgery. International Journal of Dermatology 2010;49(5): 482–91. [MEDLINE: 20534080]

Farmer 1996 Farmer ER, Gonin R, Hanna MP. Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Human Pathology 1996; 27(6):528–31. [MEDLINE: 8666360] Farshad 2002 Farshad A, Burg G, Panizzon R, Dummer R. A retrospective study of 150 patients with lentigo maligna and lentigo maligna melanoma and the efficacy of radiotherapy using Grenz or soft X-rays. British Journal of Dermatology 2002;146(6):1042–6. [MEDLINE: 12072074] Field 1995 Field LM. Cryosurgery for lentigo maligna. Journal of American Academy of Dermatology 1995;32(4):686–7. [MEDLINE: 7896972] Fogarty 2014 Fogarty GB, Hong A, Scolyer RA, Lin E, Haydu L, Guitera P, et al.Radiotherapy for lentigo maligna: a literature review and recommendations for treatment. British Journal of Dermatology 2014;170(1):52–8. [MEDLINE: 24032599] Gage 1979 Gage AA, Meenaghan MA, Natiella JR, Greene GW. Sensitivity of pigmented mucosa and skin to freezing injury. Cryobiology 1979;16(4):348–61. [PUBMED: 487851] Garbe 2008 Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, et al.Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma. Melanoma Research 2008;18(1): 61–7. [MEDLINE: 18227710] Gaspar 1997 Gaspar ZS, Dawber RP. Treatment of lentigo maligna. Australasian Journal of Dermatology 1997;38(1):1–8. [MEDLINE: 9046644] Gupta 2004 Gupta AK, Cherman AM, Tyring SK. Viral and nonviral uses of imiquimod: a review. Journal of Cutaneous Medicine & Surgery 2004;8(5):338–52. [MEDLINE: 15868314] Hemminki 2003 Hemminki K, Zhang H, Czene K. Incidence trends and familial risks in invasive and in situ cutaneous melanoma by sun-exposed body sites. International Journal of Cancer 2003;104(6):764–71. [MEDLINE: 12640685] Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org. Hill 1999 Hill DC, Gramp AA. Surgical treatment of lentigo maligna and lentigo maligna melanoma. Australasian Journal of Dermatology 1999;40(1):25–30. [MEDLINE: 10098285] Jejurikar 2007 Jejurikar SS, Borschel GH, Johnson TM, Lowe L, Brown DL. Immediate, optimal reconstruction of facial lentigo


23

maligna and melanoma following total peripheral margin control. Plastic & Reconstructive Surgery 2007;120(5): 1249–55. [MEDLINE: 17898597] Johnson 1997 Johnson TM, Headington JT, Baker SR, Lowe L. Usefulness of the staged excision for lentigo maligna and lentigo maligna melanoma: the “square” procedure. Journal of American Academy of Dermatology 1997;37(5 Pt 1):758–64. [MEDLINE: 9366823] Kang 2009 Kang HY, Park TJ, Jin SH. Imiquimod, a Toll-like receptor 7 agonist, inhibits melanogenesis and proliferation of human melanocytes. Journal of Investigative Dermatology 2009;129(1):243–6. [MEDLINE: 18596825] King 2005 King R, Page RN, Googe PB, Mihm MC. Lentiginous melanoma: a histologic pattern of melanoma to be distinguished from lentiginous nevus. Modern Pathology 2005;18(10):1397–401. [MEDLINE: 15976811] Koehler 2011 Koehler MJ, Speicher M, Lange-Asschenfeldt S, Stockfleth E, Metz S, Elsner P, et al. Clinical application of multiphoton tomography in combination with confocal laser scanning microscopy for in vivo evaluation of skin diseases. Experimental Dermatology 2011;20(7):589–94. [MEDLINE: 21539618] Kopera 1995 Kopera D. Treatment of lentigo maligna with the carbon dioxide laser. Archives of Dermatology 1995;131(6):735–6. [MEDLINE: 7778935] Kuflik 1994 Kuflik EG, Gage AA. Cryosurgery for lentigo maligna. Journal of American Academy of Dermatology 1994;31(1): 75–8. [MEDLINE: 8021376] Kunishige 2011 Kunishige JH, Brodland DG, Zitelli JA. Surgical margins for melanoma in situ. Journal of American Academy of Dermatology 2012;66(3):438–44. [MEDLINE: 22196979] Kvaskoff 2011 Kvaskoff M, Siskind V, Green AC. Risk Factors for Lentigo Maligna Melanoma Compared With Superficial Spreading Melanoma: A Case-Control Study in Australia. Archives of Dermatology 2012;148(2):164–70. [MEDLINE: 22004881] Lee 2008 Lee MR, Ryman WJ. Treatment of lentigo maligna with total circumferential margin control using vertical and horizontal permanent sections: a retrospective study. Australasian Journal of Dermatology 2008;49(4):196–201. [MEDLINE: 18855780] Lee 2011 Lee H, Sowerby LJ, Temple CL, Yu E, Moore CC. Carbon dioxide laser treatment for lentigo maligna: a retrospective review comparing 3 different treatment modalities. Archives

of Facial Plastic Surgery 2011;13(6):398–403. [MEDLINE: 22106185] Leibl 1985 Leibl H, Stingl G, Pehamberger H, Korschan H, Konrad K, Wolff K. Inhibition of DNA synthesis of melanoma cells by azelaic acid. Journal of Investigative Dermatology 1985;85 (5):417–22. [MEDLINE: 4056455] Litwin 1975 Litwin MS, Krementz ET, Mansell PW, Reed RJ. Topical chemotherapy of lentigo maligna with 5-fluorouracil. Cancer 1975;35(3):721–33. [MEDLINE: 1111940] Madan 2009 Madan V, August PJ. Lentigo maligna-outcomes of treatment with Q-switched Nd:YAG and alexandrite lasers. Dermatological Surgery 2009;35(4):607–11. [MEDLINE: 19309345] Mahoney 2005 Mahoney MH, Joseph M, Temple CL. The perimeter technique for lentigo maligna: an alternative to Mohs micrographic surgery. Journal of Surgical Oncology 2005;91 (2):120–5. [MEDLINE: 16028282] McKenna 2006 McKenna JK, Florell SR, Goldman GD, Bowen GM. Lentigo maligna/lentigo maligna melanoma: current stage of diagnosis and treatment. Dermatological Surgery 2006;32 (4):493–504. [MEDLINE: 16681656] McLeod 2011 McLeod M, Choudhary S, Giannakakis G, Nouri K. Surgical Treatments for Lentigo Maligna: A Review. Dermatologic Surgery 2011; Vol. 37, issue 9:1210–28. [MEDLINE: 21631635] Megahed 2002 Megahed M, Schön M, Selimovic D, Schön MP. Reliability of diagnosis of melanoma in situ. Lancet 2002; 359(9321):1921–2. [MEDLINE: 12057558] Mirzoyev 2014 Mirzoyev SA, Knudson RM, Reed KB, Hou JL, Lohse CM, Frohm ML, et al.Incidence of lentigo maligna in Olmsted County, Minnesota, 1970 to 2007. Journal of the American Academy of Dermatology 2014;70(3):443–8. [MEDLINE: 24373777] Mocellin 2011 Mocellin S, Nitti D. Cutaneous melanoma in situ: translational evidence from a large population-based study. Oncologist 2011;16(6):896–903. [MEDLINE: 21632457] Mohs 1941 Mohs FE. Chemosurgery: a microscopically controlled method of cancer excision. Archives of Surgery 1941;42(2): 279–95. National Comprehensive Cancer Network 2009 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma. www.nccn.org/professionals/physician˙gls/PDF/ melanoma.pdf (accessed 12 January 2011).


24

National Institutes of Health 1993 National Institutes of Health. National Institutes of Health Consensus Development Conference Statement on Diagnosis and Treatment of Early Melanoma, January 2729, 1992. American Journal of Dermatopathology 1993;15 (1):34–43. [MEDLINE: 8434730] Osborne 2002 Osborne JE, Hutchinson PE. A follow-up study to investigate the efficacy of initial treatment of lentigo maligna with surgical excision. British Journal of Plastic Surgery 2002;55(8):611–5. [MEDLINE: 12550112]

Stevenson 2005 Stevenson O, Ahmed I. Lentigo maligna: prognosis and treatment options. American Journal of Clinical Dermatology 2005;6(3):151–64. [MEDLINE: 15943492] Swetter 2005 Swetter SM, Boldrick JC, Jung SY, Egbert BM, Harvell JD. Increasing incidence of lentigo maligna melanoma subtypes: northern California and national trends 19902000. Journal of Investigative Dermatology 2005;125(4): 685–91. [MEDLINE: 16185266]

Rajpar 2006 Rajpar SF, Marsden JR. Imiquimod in the treatment of lentigo maligna. British Journal of Dermatology 2006;155 (4):653–6. [MEDLINE: 16965411]

Tannous 2000 Tannous ZS, Lerner LH, Duncan LM, Mihm MC, Flotte TJ. Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type. Human Pathology 2000;31(6):705–8. [MEDLINE: 10872664]

Ray 2005 Ray CM, Kluk M, Grin CM, Grant-Kels JM. Successful treatment of malignant melanoma in situ with topical 5% imiquimod cream. International Journal of Dermatology 2005;44(5):428–34. [MEDLINE: 15869545]

Tsang 1994 Tsang RW, Liu FF, Wells W, Payne DG. Lentigo maligna of the head and neck: results of treatment by radiotherapy. Archives of Dermatology 1994;130(8): 1008–12. [MEDLINE: 8053696]

Review Manager 2014 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Vereecken 2002 Vereecken P, Heenen M. Recurrent lentigo maligna melanoma: regression associated with local azelaic acid 20%. International Journal of Clinical Practice 2002;56(1): 68–9. [MEDLINE: 11831841]

Rodriguez Prieto 1993 Rodriguez Prieto MA, Manchado Lopez P, Ruiz Gonzalez I, Suarez D. Treatment of lentigo maligna with azelaic acid. International Journal of Dermatology 1993;32(5):363–4. [MEDLINE: 8505164] Ryan 1988 Ryan RF, Krementz ET, Litwin MS. A role for topical 5-fluorouracil therapy in melanoma. Journal of Surgical Oncology 1988;38(4):250–6. [MEDLINE: 3045424] Schiffner 2000 Schiffner R, Schiffner-Rohe J, Vogt T, Landthaler M, Wlotzke U, Cognetta AB, et al.Improvement of early recognition of lentigo maligna using dermatoscopy. Journal of the American Academy of Dermatology 2000;42(1 Pt 1): 25–32. [MEDLINE: 10607316] Schmid-Wendtner 2000 Schmid-Wendtner MH, Brunner B, Konz B, Kaudewitz P, Wendtner CM, Peter RU, et al.Fractionated radiotherapy of lentigo maligna and lentigo maligna melanoma in 64 patients. Journal of American Academy of Dermatology 2000; 43(3):477–82. [MEDLINE: 10954659] Shriner 1998 Shriner DL, McCoy DK, Goldberg DJ, Wagner RF. Mohs micrographic surgery. Journal of American Academy of Dermatology 1998;39(1):79–97. [MEDLINE: 9674401] Sladden 2009 Sladden MJ, Balch C, Barzilai DA, Berg D, Freiman A, Handiside T, et al.Surgical excision margins for primary cutaneous melanoma. Cochrane Database of Systematic Reviews 2009, Issue 4. [DOI: 10.1002/ 14651858.CD004835.pub2]

Walling 2007 Walling HW, Scupham RK, Bean AK, Ceilley RI. Staged excision versus Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma. Journal of the American Academy of Dermatology 2007;57(4):659–64. [MEDLINE: 17870430] Weinstock 1987 Weinstock MA, Sober AJ. The risk of progression of lentigo maligna to lentigo maligna melanoma. British Journal of Dermatology 1987;116(3):303–10. [MEDLINE: 3567069] Woodmansee 2009 Woodmansee CS, McCall MW. Recurrence of lentigo maligna and development of invasive melanoma after treatment of lentigo maligna with imiquimod. Dermatologic Surgery 2009;35(8):1286–9. [MEDLINE: 19438661] Zitelli 1997 Zitelli JA, Brown C, Hanusa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. Journal of American Academy of Dermatology 1997;37(2 Pt 1):236–45. [MEDLINE: 9270510]

References to other published versions of this review Apalla 2013 Apalla Z, Tzellos T, Kyrgidis A, Mocellin S, Chan AW, Haque Hussain S, Pilati P. Interventions for melanoma in situ, including lentigo maligna. Cochrane Database of Systematic Reviews 2013, Issue 1. [DOI: 10.1002/ 14651858.CD010308] ∗ Indicates the major publication for the study


25

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID] Hyde 2012 Methods

Design: Prospective, single centre, randomised, open label, parallel with 2 treatment arms

Participants

Inclusion criteria: biopsy-confirmed lentigo maligna participants 90 patients (24 women, 66 men) with histologically proven lentigo maligna, mean age = 68.2 years

Interventions

2 treatments groups: • First group: shave excision of visible tumour followed by imiquimod 5% cream 5 days/week (from Monday to Friday) plus tazarotene 0.1% gel 2 days/week (Saturday and Sunday) for 3 months • Second group: shave excision of visible tumour followed by imiquimod 5% cream 5 days/week (from Monday to Friday) for 3 months Participants in all groups treated an area extending 1 inch (2.54 cm) beyond the outlined tumour margins 2 months after cessation of topical treatment, the initial tumour footprint was excised using 2 mm margins via a staged excision with radial frozen sections and melan-A immunostaining to confirm negative margins

Outcomes

Primary outcome: • Histological complete response (histological complete clearance), 5 months after initiation of treatment Secondary outcomes: • Local recurrence rate • Progression to invasive melanoma • Discontinuation of treatment because of harms, the first 3 months after initiation of treatment • Overall inflammation score (inflammatory response), the first 3 months after initiation of treatment

Notes

Trial registration: clinicaltrials.gov, identifier: NCT00707174 Financial disclosure: none Institution: Huntsman Cancer Institute, the university of Utah, USA

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Low risk bias)

The study used an 1:1 random number table for 2 interventions generated by the clinical trials office at the institution

Allocation concealment (selection bias)

The study used a centralised service

Low risk


26

Hyde 2012

(Continued)

Blinding of participants and personnel High risk (performance bias) All outcomes

Study participants, medical staff, and study staff were not blinded after the assignment was made

Blinding of outcome assessment (detection High risk bias) All outcomes

Study stuff were not blinded after the assignment was made

Incomplete outcome data (attrition bias) All outcomes

High risk

5/46 participants from the imiquimodalone group withdrew, 7/44 participants from the imiquimod-tazarotene group withdrew: reasons partially provided, not intention-to-treat analysis

Selective reporting (reporting bias)

Low risk

The trial reported all prespecified outcomes

Definition of incomplete response

Low risk

The study clearly defined incomplete response, and the definitions were sufficient

Similarity of groups at baseline

Unclear risk

Although we deemed the randomisation process as sufficient and correct, the study authors did not present baseline important characteristics of the 2 groups

Duration of follow-up period

Low risk

We deemed the duration of follow-up period as adequate (mean follow-up period of 42 months)

Method of follow-up (first 5 months)

Low risk

We deemed the method of follow-up period for the first 5 months as adequate

Method of follow-up (after the first 5 High risk months)

We deemed the method of follow-up as insufficient

Definition of local recurrence

We deemed the definition of local recurrence as insufficient

High risk

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Chagpar 2007

There was no comparison of treatments

Khayat 2003

There were no participants with melanoma in situ


27

(Continued)

Kim 2008

There were no participants with melanoma in situ

Morganroth 2009

There was no comparison of treatments

Characteristics of studies awaiting assessment [ordered by study ID] Amatetti 1994 Methods

This was a randomised controlled trial

Participants

Participants diagnosed with non-metastatic melanoma

Interventions

Not fully known; adjuvant therapy with recombinant interferon alpha is reported

Outcomes

Not known

Notes

Some parameters of this trial remain unknown because contact with the study authors was not fruitful

Foster 2007 Methods

This was a randomised controlled trial

Participants

Participants diagnosed with superficial melanoma

Interventions

Group A: horizontal “en face” Mohs tissue processing Group B: vertical “breadloaf ” tissue processing

Outcomes

Not known

Notes

Some parameters of this trial remain unknown because contact with the study authors was not fruitful

Characteristics of ongoing studies [ordered by study ID] NCT01720407 Trial name or title

Relevance of Imiquimod as Neo-adjuvant Treatment to Reduce Excision Size and the Risk of Intralesional Excision in Lentigo Maligna of the Face (ImiReduc)

Methods

This is a randomised, parallel group, 2-arm, open label trial

Participants

Inclusion criteria of the trial: Participants from both sexes aged over 18 years and operable, presenting with LM of the face or the neck, histologically confirmed by biopsy (primitive lesion, of a surface ≥ to 1.5 cm² and ≤ to 20 cm², with the possibility of graft or flap reconstruction)


28

NCT01720407

(Continued)

Interventions

Group A: imiquimod (5 times per week) applied to and extending 1 cm beyond the lesion for a period of 4 weeks, followed by surgery performed 4 weeks after the last application of the topical treatment Group B: vehicle (5 times per week) applied to and extending 1 cm beyond the lesion for a period of 4 weeks, followed by surgery performed 4 weeks after the last application of the topical treatment

Outcomes

Primary outcomes: 1. Margin of resection. Successful resection with proper margins is defined by an at least 5 mm healthy tissue margin beyond lesion periphery Secondary outcomes: 1. The number of surgical re-excisions required to obtain complete remission 2. The number of recurrences, defined as the reappearance of pigmentation within 3 years of surgical excision 3. The number of histologically confirmed complete remissions under imiquimod

Starting date

October 2012

Contact information

Dr Amir Khammari, [email protected]

Notes

Sponsor: MEDA Pharma GmbH & Co. KG

LM = lentigo maligna.


29

DATA AND ANALYSES

Comparison 1. Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna

No. of studies

Outcome or subgroup title 1 Primary outcome: Histological complete response (ITT) 2 Primary outcome: Histological complete response (available-case analysis) 3 Secondary outcome: Discontinuation of treatment because of harms 4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study 5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants 6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3)

No. of participants

Statistical method

Effect size

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

1


Totals not selected

1


Totals not selected

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

1


Totals not selected

Analysis 1.1. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 1 Primary outcome: Histological complete response (ITT). Review:

Interventions for melanoma in situ, including lentigo maligna

Comparison: 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna Outcome: 1 Primary outcome: Histological complete response (ITT)

Study or subgroup

Hyde 2012

Imiquimod and tazarotene

Imiquimod

n/N

n/N

29/44

27/46

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 1.12 [ 0.81, 1.55 ]

0.1 0.2

0.5

Favours monotherapy


1

2

5

10

Favours combination

30

Analysis 1.2. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 2 Primary outcome: Histological complete response (available-case analysis). Review:


Comparison: 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna Outcome: 2 Primary outcome: Histological complete response (available-case analysis)

Study or subgroup

Hyde 2012


Imiquimod

n/N

n/N

29/37

27/41

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 1.19 [ 0.90, 1.57 ]

0.02

0.1

1

Favours monotherapy

10

50

Favours combination

Analysis 1.3. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 3 Secondary outcome: Discontinuation of treatment because of harms. Review:


Comparison: 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna Outcome: 3 Secondary outcome: Discontinuation of treatment because of harms

Study or subgroup

Hyde 2012


Imiquimod

n/N

n/N

6/44

1/46

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 6.27 [ 0.79, 50.02 ]

0.002

0.1

Favours combination


1

10

500

Favours monotherapy

31

Analysis 1.4. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study. Review:


Comparison: 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna Outcome: 4 Secondary outcome: Inflammatory response (overall Inflammation score) for participants who finished study

Study or subgroup

Hyde 2012


Mean Difference

Imiquimod

N

Mean(SD)

N

Mean(SD)

37

2.297 (0.9)

42

1.74 (0.989)

Mean Difference

IV,Random,95% CI

IV,Random,95% CI 0.56 [ 0.14, 0.98 ]

-1

-0.5

0

0.5

Favours combination

1

Favours monotherapy

Analysis 1.5. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants. Review:


Comparison: 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna Outcome: 5 Secondary outcome: Inflammatory response (overall Inflammation score) for all participants

Study or subgroup

Hyde 2012


Mean Difference

Imiquimod

N

Mean(SD)

N

Mean(SD)

44

2.3 (0.93)

44

1.7 (1)

IV,Fixed,95% CI

IV,Fixed,95% CI 0.60 [ 0.20, 1.00 ]

-2

-1

Favours combination


Mean Difference

0

1

2

Favours monotherapy

32

Analysis 1.6. Comparison 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna, Outcome 6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3). Review:


Comparison: 1 Imiquimod 5% cream with versus without tazarotene 0.1% gel for the treatment of lentigo maligna Outcome: 6 Secondary outcome: Inflammatory response (number of lesions with grade 2 or 3)

Study or subgroup

Hyde 2012


Imiquimod

n/N

n/N

36/44

26/44

Risk Ratio

Risk Ratio

M-H,Fixed,95% CI

M-H,Fixed,95% CI 1.38 [ 1.04, 1.84 ]

0.1 0.2

0.5

Favours combination

1

2

5

10

Favours monotherapy

ADDITIONAL TABLES Table 1. Glossary of medical terms

Medical term

Explanation

Intraepidermal

something confined within the epidermis

Preinvasive

a malignant tumour that remains constricted in the epithelium, while the dermo-epidermal junction preserves its integrity

Eschar

a dry scab or slough formed on the skin as a result of a burn or by the action of a corrosive or caustic substance

Invasive

a malignant tumour that breaks the dermo-epidermal junction and invades the dermis

Lentigo maligna

a subtype of preinvasive intraepidermal melanoma, associated specifically with chronic solar exposure

Vehicle

an excipient or a menstruum, a substance, usually without therapeutic action, used as a medium to give bulk for the administration of medicines

Apoptosis

a genetically directed process of cell self-destruction that is marked by the fragmentation of nuclear DNA. It is activated either by the presence of a stimulus or removal of a suppressing agent or stimulus, and is a normal physiological process eliminating DNA-damaged, superfluous, or unwanted cells. It is a synonym for programmed cell death

Actinic keratosis

rough, scaly macule or patch of skin that it is considered precancerous and is associated with chronic sun exposure


33

Table 1. Glossary of medical terms

(Continued)

Lentigo senilis

a flat brownish, pigmented spot on the skin, due to increased deposition of melanin and an increased number of melanocytes

Seborrheic keratosis

a benign skin tumour that occurs singly or in clusters on the surface of the skin, is usually light to dark brown or black in colour, and typically has a warty texture often with a waxy appearance

Patch

a greater than 1 cm circumscribed area of discolouration on the skin

Cytokine

a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells, or on the behavior of cells

Innate immunity

immunity that occurs naturally as a result of a person’s genetic constitution or physiology and does not arise from a previous infection or vaccination

Blinding

the concealment of group assignment - to either the treatment or control group - from the knowledge of participants, investigators in a clinical trial, or both

Tumour islands

aggregates of tumour cells

APPENDICES Appendix 1. Skin Group Specialised Register search strategy #1 ((“Lentiginous melanoma” or “melanotic and freckle*” or “lentigo* maligna*” or “melanoma in situ” or “malignant freckle*” or “hutchinson* freckle*”) OR (hutchinson’s melanotic freckle):MH OR (Carcinoma in Situ):MH) AND ( INREGISTER)

Appendix 2. CENTRAL (Cochrane Library) search strategy #1 MeSH descriptor: [Carcinoma in Situ] explode all trees #2 MeSH descriptor: [Skin] explode all trees #3 MeSH descriptor: [Skin Neoplasms] explode all trees #4 MeSH descriptor: [Melanoma] explode all trees #5 #2 or #3 or #4 #6 #1 and #5 #7 MeSH descriptor: [Hutchinson’s Melanotic Freckle] explode all trees #8 Lentiginous melanoma #9 melanotic and freckle* #10 lentigo* maligna* #11 melanoma in situ #12 circumscribed precancerous melanosis #13 melanosis circumscripta precancerosa #14 malignant and freckle* #15 hutchinson* and freckle* #16 {or #6-#15} Interventions for melanoma in situ, including lentigo maligna (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

34

Appendix 3. MEDLINE (Ovid) search strategy 1. exp Carcinoma in Situ/ 2. exp Skin/ 3. exp Skin Neoplasms/ 4. exp Melanoma/ 5. 2 or 3 or 4 6. 1 and 5 7. exp Hutchinson’s Melanotic Freckle/ 8. “Lentiginous melanoma”.mp. 9. (melanotic and freckle$1).mp. 10. (lentigo$1 and maligna$2).mp. 11. (melanoma and “in situ$”).mp. 12. circumscribed precancerous melanosis.mp. 13. melanosis circumscripta precancerosa.mp. 14. (malignant and freckle$1).mp. 15. (hutchinson$2 and freckle$1).mp. 16. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 17. randomized controlled trial.pt. 18. controlled clinical trial.pt. 19. randomized.ab. 20. placebo.ab. 21. clinical trials as topic.sh. 22. randomly.ab. 23. trial.ti. 24. 17 or 18 or 19 or 20 or 21 or 22 or 23 25. exp animals/ not humans.sh. 26. 24 not 25 27. 16 and 26

Appendix 4. Embase (Ovid) search strategy 1. exp carcinoma in situ/ 2. exp skin/ 3. exp melanoma/ 4. exp skin tumor/ 5. 2 or 3 or 4 6. 1 and 5 7. “Lentiginous melanoma”.mp. 8. (melanotic and freckle$1).mp. 9. (lentigo$1 and maligna$2).mp. 10. (melanoma and “in situ$”).mp. 11. exp malignant lentigo/ 12. circumscribed precancerous melanosis.mp. 13. melanosis circumscripta precancerosa.mp. 14. (malignant and freckle$1).mp. 15. (hutchinson$2 and freckle$1).mp. 16. 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 17. crossover procedure.sh. 18. double-blind procedure.sh. 19. single-blind procedure.sh. 20. (crossover$ or cross over$).tw. 21. placebo$.tw. Interventions for melanoma in situ, including lentigo maligna (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

35

22. (doubl$ adj blind$).tw. 23. allocat$.tw. 24. trial.ti. 25. randomized controlled trial.sh. 26. random$.tw. 27. or/17-26 28. exp animal/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/ 29. human/ or normal human/ 30. 28 and 29 31. 28 not 30 32. 27 not 31 33. 16 and 32

Appendix 5. LILACS search strategy “Lentiginous melanoma” or “melanotic and freckle$” or “lentigo$ maligna$” or “melanoma in situ” or “malignant freckle$” or “hutchinson$ freckle$” or “lentigo maligno”

Appendix 6. African index Medicus, IndMED and IMSEAR search strategy “Randomized controlled trial” OR “controlled clinical trial” AND “lentigo maligna” OR “lentigo maligna melanoma” OR “Hutchinson Melanotic Freckle” OR “melanoma in-situ” OR “melanoma in situ” OR “melanoma-in-situ”

CONTRIBUTIONS OF AUTHORS TT was the contact person with the editorial base. TT and AK co-ordinated contributions from the co-authors and wrote the final draft of the review. TT and AK screened papers against eligibility criteria. TT and AK obtained data on ongoing and unpublished studies. TT and AK appraised the quality of papers. TT and AK extracted data for the review and sought additional information about papers. TT and AK entered data into RevMan. TT and AK (with the help of all authors) analysed and interpreted data. TT and AK worked on the methods sections. ZA and TT drafted the clinical sections of the background and responded to the clinical comments of the referees. TT and AK (with the help of all authors) responded to the methodology and statistics comments of the referees. PP was the consumer co-author and checked the review for readability and clarity, as well as ensuring outcomes are relevant to consumers. TT is the guarantor of the update. Disclaimer The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health, UK.


36

DECLARATIONS OF INTEREST Thrasivoulos Tzellos: Nothing to declare. Athanassios Kyrgidis: Nothing to declare. Simone Mocellin: Nothing to declare. An-Wen Chan: Nothing to declare. Pierluigi Pilati: Nothing to declare. Zoe Apalla: Nothing to declare.

SOURCES OF SUPPORT Internal sources • Dessau Medical Center, Dessau, Germany. Provided internet facilities • Freie Universität Berlin, Germany. Provided online literature • Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. Provided internet facilities and online literature • Hospital of Skin and Venereal Diseases, Thessaloniki, Greece. Provided internet facilities • Women’s College Research Institute, University of Toronto, Toronto, Canada. Provided internet facilities and online literature • University Hospital of North Norway, Harstad, Troms, Norway. Provided internet facilities and online literature

External sources • The National Institute for Health Research (NIHR), UK. The NIHR, UK, is the largest single funder of the Cochrane Skin Group.

DIFFERENCES BETWEEN PROTOCOL AND REVIEW The order of authors in the byline has changed after agreement with all authors; we changed the contact author, and the new contact author is Thrasivoulos Tzellos. In our protocol, we reported that a ’Summary of findings’ table would include only primary outcomes. We decided to include both primary and secondary outcomes for reasons of better readability and presentation, since there was only one study included. With regard to ’Types of outcome measures’, we decided to swap our primary and secondary outcomes so ’Histological or clinical complete clearance rate’ is now our first primary outcome, and ’Clinical or histological local recurrence rate’ is our first secondary outcome. The reasons for this change, which was a unanimous decision, were 1) In order for recurrence rate to be measurable, a complete clearance rate is a prerequisite, 2) we identified no outcomes pertaining to ’Clinical or histological local recurrence rate’ in this instance of the review. After discussion with all authors, we rephrased ’Histological or clinical complete clearance rate’ as ’Histological or clinical complete response rate’, because this is a more common and universal way of expressing this outcome in oncology. The nature of the outcome did not change with this modification; however, we feel that readability has increased. Taking into account the mechanism of action of the treatments used in the included studies, we added ’Inflammatory response’ as a secondary outcome to Types of outcome measures. Interventions for melanoma in situ, including lentigo maligna (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

37

INDEX TERMS Medical Subject Headings (MeSH) Aminoquinolines [administration & dosage]; Antineoplastic Agents [∗ administration & dosage]; Antineoplastic Combined Chemotherapy Protocols [administration & dosage]; Combined Modality Therapy [methods]; Hutchinson’s Melanotic Freckle [∗ therapy]; Melanoma [∗ therapy]; Nicotinic Acids [administration & dosage]; Randomized Controlled Trials as Topic; Skin Neoplasms [∗ therapy]

MeSH check words Female; Humans; Male


38

Johnson square procedure for lentigo maligna and lentigo maligna melanoma.

Treatment of lentigo maligna and lentigo maligna melanoma.

Synchronous conjunctival melanoma and lentigo maligna melanoma.

Reviewing Challenges in the Diagnosis and Treatment of Lentigo Maligna and Lentigo-Maligna Melanoma.

Proceedings: Lentigo-maligna melanoma: an ultrastructural study.

Imiquimod 5% cream as primary or adjuvant therapy for melanoma in situ, lentigo maligna type.

Contoured technique for lentigo maligna.

Very Rare Amelanotic Lentigo Maligna Melanoma with Skull Roof Invasion.

Lentigo maligna and lentigo maligna melanoma as occupational skin diseases in a forestry worker with long-standing occupational UV-exposure.

Clinicopathological characteristics of 270 patients with lentigo maligna and lentigo maligna melanoma: data from a German skin cancer centre.

Staged Excision for Lentigo Maligna and Lentigo Maligna Melanoma: Analysis of Surgical Margins and Long-term Recurrence in 68 Cases from a Single Practice.

Mohs micrographic surgery for lentigo maligna and lentigo maligna melanoma using Mel-5 immunostaining: an update from the University of Minnesota.

Naevus-associated lentigo maligna: coincidence or continuum?

Lentigo maligna mimicking invasive melanoma in Mohs surgery: a case report.

Lentigo Maligna Melanoma With Local and Distant Blue Nevus-like Metastases.

Lentigo maligna melanoma with a history of cosmetic treatment: Prevalence, surgical outcomes and considerations.

Macromelanosomes: their significantly greater presence in the margins of a lentigo maligna versus solar lentigo.

Surveillance for treatment failure of lentigo maligna with dermoscopy and in vivo confocal microscopy: new descriptors.

Combination topical therapy for conjunctival primary acquired melanosis with atypia and periocular lentigo maligna.

Time to local recurrence of lentigo maligna: Implications for future studies.

Handheld reflectance confocal microscopy to aid in the management of complex facial lentigo maligna.

Early dermoscopic detection of lentigo maligna within a lesion of pigmented contact dermatitis.

In vivo reflectance confocal microscopy to optimize the spaghetti technique for defining surgical margins of lentigo maligna.

Age, gender, and topography influence the clinical and dermoscopic appearance of lentigo maligna.