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Study |

Efficacy of Imiquimod Cream, 5%, for Lentigo Maligna After Complete Excision:  A Study of 43 Patients FREE

Lena Ly, MBBS; John William Kelly, MBBS, FACD, MD; Rodney O ’Keefe, MBBS, FRCPA; Tina Sutton, BSc, BMBS; John P. Dowling, MBBS, FRCPA; Sarah Swain, MBBS, FRCPA; Marguerite Byrne, MBBS; Nathan Curr, MBBS; Rory Wolfe, BSc, PhD; Alex Chamberlain, MBBS, FACD; Martin Haskett, MBBS, FACD
[+] Author Affiliations

Author Affiliation: Victorian Melanoma Service (Drs Ly, Kelly, Sutton, Dowling, Swain, Byrne, Curr, Chamberlain, and Haskett) and Department of Anatomical Pathology (Drs Dowling and Swain), Alfred Health, and Departments of Medicine (Dr Kelly) and Epidemiology and Preventive Medicine, Monash University (Dr Wolfe), Melbourne; Dermpath Pty Ltd, East Ivanhoe (Dr O ’Keefe); Skin and Cancer Foundation, Carlton (Dr Sutton); Anatomical Pathology, Peter MacCallum Institute, East Melbourne (Dr Swain); and Department of Anaesthetics, Fremantle Hospital and Health Service, Fremantle (Dr Curr), Australia.


Arch Dermatol. 2011;147(10):1191-1195. doi:10.1001/archdermatol.2011.260.
Text Size: A A A
Published online

Objective To determine the efficacy of imiquimod cream, 5%, in the treatment of lentigo maligna (LM).

Design Open-label before-and-after interventional study.

Setting A multidisciplinary melanoma clinic at a major tertiary hospital.

Patients Forty-three patients with biopsy-proven LM of greater than 5 mm in diameter completed this study.

Interventions Imiquimod cream, 5%, was applied to the lesion 5 days a week for 12 weeks. The original lesion was excised with a 5-mm margin.

Main Outcome Measures The primary outcome was histopathologic evidence of LM in the excision specimen assessed independently by 2 of 3 dermatopathologists. Visible inflammation during treatment and macroscopic clearance were recorded.

Results When 5 of the 43 patients with discordant histopathologic assessment of the excision specimen were excluded, 20 of 38 patients (53% [95% confidence interval, 36%-69%]) demonstrated histopathologic clearance of LM after imiquimod treatment. Visible inflammation was significantly associated with histopathologic clearance (P  =  .04), but the positive predictive value was low (62%). Macroscopic clearance showed some association with histopathologic clearance (P  =  .11). Dermatopathologist concordance for all 43 specimens was substantial ( κ  =  0.77; 95% confidence interval, 0.57-0.96).

Conclusions Imiquimod cream, 5%, has limited efficacy in the treatment of LM when determined by histopathologic assessment of the entire treated area. The clinical signs of visible inflammation during treatment and apparent lesion clearance cannot be relied on to assess efficacy.

Trial Registration anzctr.org.au Identifier: ACTRN12610000066088

Figures in this Article

Researchers and dermatologists have shown considerable interest in imiquimod cream, 5% (Aldara; Graceway Pharmaceuticals, LLC, St Paul, Minnesota), in the treatment of lentigo maligna (LM), with 12 case series reporting variable response rates ranging from 67% through 100%.112 The methods used in these series are highly variable, and some do not acknowledge the limitations regarding macroscopic or histopathologic assessment of LM and its margins. Significant interobserver variation between pathologists when delineating the edge of LM as distinct from adjacent changes of melanocytic hyperplasia in sun-damaged skin has been reported.1315 Inherent difficulties in histopathologic assessment are further compounded when partial biopsy is performed.1618 This study was planned to minimize these limitations by treating the entire lesion and a surrounding margin of healthy skin with imiquimod cream, 5%, then performing standard wide local excision and histopathologic assessment of the entire treated area. To minimize observer error, 2 of 3 expert dermatopathologists (J.P.D., or S.S., and R.O.) reviewed the initial diagnostic and postintervention specimens.

This study was approved by the Alfred Hospital Human Research Ethics Committee. It was designated Project No. 174-03.

CASE SELECTION

This was an open-label nonrandomized before-and-after interventional study conducted at the Victorian Melanoma Service outpatient clinic at the Alfred Hospital. All patients aged 18 to 90 years with LM greater than 5 mm in diameter and referred to this service from March 1, 2004, through October 31, 2009, were invited to participate after agreement regarding the initial diagnostic biopsy finding by 2 of 3 dermatopathologists (J.P.D., S.S., and R.O.) (Figure 1). Patients were excluded if they were unable to consent; were pregnant, breastfeeding, or immunocompromised; or had lesions involving the lips, eyelids, or any mucus membranes. Anatomic sites for all lesions treated are shown in Figure 2.

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Figure 1. Schematic study flowchart.

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Figure 2. Anatomical distribution of the 43 lesions treated. Numbers indicate numbers of patients.

EXPERIMENTAL DESIGN
Diagnosis, Lesion Site, and Margin Definition

A clinical diagnosis of LM was made and histopathologically confirmed with results of shave or punch biopsies using hematoxylin-eosin stains assessed independently by 2 of 3 dermatopathologists (J.P.D., S.S., and R.O.). Clinical margins were determined using a Wood lamp, and mapping biopsy specimens were taken when uncertainty existed as to the extent of the lesion. The clinical margins of the first 13 lesions were marked with a tattoo to inform subsequent wide local excision, but because the inflammatory response occasionally caused the disappearance of the tattoo ink before surgery, subsequent lesions were marked with a surgical marking pen (Acculine Engineering, Inc, Waterbury, Connecticut) and photographed (Nikon 4500 COOLPIX S9 camera; Nikon Corporation, Tokyo, Japan).

Treatment Protocol

Patients were instructed to apply imiquimod cream, 5%, to cover the lesion and 1 cm beyond its margin, massaging the cream in until invisible, once daily, Monday through Friday, for 12 weeks. They were instructed to apply nothing else to the area for the next 8 hours. The 12-week period was chosen to equate with the longest periods of imiquimod treatment used for management of basal cell carcinoma and to limit the period for which patients had to tolerate inflammation. Patients were instructed to take rest periods whenever the patient or treating dermatologist judged there was excessive inflammation, defined as marked discomfort, weeping or crusting of the lesion, or epidermal erosion. Patients were instructed to recommence application of the cream when this inflammation subsided. All patients undergoing evaluation completed a total treatment period of 12 weeks including rest periods.

Wide Local Excision

Wide local excision was planned to occur within 4 weeks of completion of imiquimod treatment and was performed after complete resolution of macroscopic inflammation. A standard 5-mm margin was added to the pretreatment lesion markings as determined by the tattoo or pretreatment photographs.

MAIN OUTCOME MEASURES

The same dermatologist (M.H.) assessed and recorded the severity of inflammation at least monthly, and after 12 weeks of treatment, he assessed the treatment site visually using loupe magnification, dermoscopy, and the Wood lamp. The presence of residual pigmentation was recorded. The entire wide local excision specimen was serially sectioned and histopathologically assessed with hematoxylin-eosin stains by 2 of 3 dermatopathologists (J.P.D., S.S., and R.O.). Residual LM was defined by the presence of a proliferation of atypical melanocytes arranged as single cells or nests along the basal epidermis or appendages (ie, extension down the follicular epithelium or eccrine ducts). We assessed the interpathologist concordance rate.

STATISICAL ANALYSIS

We used commercially available software (Stata, release 11; StataCorp LP, College Station, Texas) to conduct all analyses. An exact binomial confidence interval (CI) was calculated for histopathologic efficacy. We used χ2 tests to assess the statistical significance (defined as P   <  .05) of associations of macroscopic clearance and inflammation with histopathologic clearance. We also calculated the sensitivity and specificity of macroscopic clearance and inflammation as a marker for identifying histopathologic clearance. We used the methods of Landis and Koch19 to interpret κ statistics for interpathologist agreement and we calculated normal-theory CIs for κ values from 1000 bootstrap resamples of the data.

Forty-eight patients were enrolled and 5 withdrew, leaving 43 who completed the study. The withdrawals occurred due to intolerable local inflammation (n  =  3), regional reactive adenopathy at 4 weeks of treatment (n  =  1), and an unrelated fatal cerebrovascular accident (n  =  1).

Of the 43 patients who completed the study, there were 24 women (56%) and 19 men (44%) (male to female ratio, 1:1.26). Women had a mean age of 69 (range, 48-83) years; men, 64 (range, 37-90) years. All lesions were on the head and neck (Figure 2). The local inflammatory reaction induced by the treatment was generally well tolerated and easily managed with symptomatic measures that included rest, cool compresses, acetaminophen (paracetamol), and topical application of petroleum jelly.

Discordance between the 3 dermatopathologists when assessing the 43 reexcision specimens as to the presence or absence of melanoma in the wide local excision specimen occurred for 5 specimens ( κ  =  0.77; 95% CI, 0.57-0.96), and the results for these 5 patients were excluded from the following analyses regarding efficacy.

Quiz Ref IDTwenty of 38 patients (53% [95% CI, 36%-69%]) demonstrated histopathologic clearance after assessment of the wide local excision. To determine whether clinical features could be used to predict efficacy, we examined the relationships between macroscopic clearance at the end of 12 weeks of treatment and visible inflammation during the 12 weeks of treatment against histopathologic clearance.

We found only weak evidence of an association between complete macroscopic and histopathologic clearance (P  =  .11; positive predictive value [PPV], 65%). Of the 20 patients with complete macroscopic clearance, 7 did not have histopathologic clearance of tumor (Figure 3A and B and Table 1). Conversely, of the 18 patients with incomplete macroscopic clearance, 7 had histopathologic clearance of tumor (Figure 3C and D and Table 1).

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Figure 3. Representative photographs of the results of treatment of lentigo maligna (LM) with imiquimod cream, 5%. A, Clinical appearance before treatment (left cheek). B, After treatment, complete macroscopic clearance without histopathologic clearance. C, Clinical appearance before treatment (left temple). D, After treatment, incomplete macroscopic clearance (residual pigment) with histopathologic clearance (evidence of histopathologic pigment incontinence). E, Clinical appearance before treatment (right cheek). F, At the end of treatment at week 12, strong visible inflammation without histopathologic clearance.

Table Graphic Jump LocationTable 1. Inflammation and Clearance in 38 Patients Treated With Imiquimod Cream, 5%

Some evidence was observed of an association between visible inflammation and histopathologic clearance (P  =  .04; PPV, 62%). Of the 29 patients with visible inflammation, 11 did not have histopathologic clearance of tumor (Figure 3E and F and Table 1). Conversely, of the 9 patients without visible inflammation, 2 patients had histopathologic clearance of tumor (Table 1).

In summary, macroscopic clearance showed moderate sensitivity and specificity as a marker for identifying histopathologic clearance (65% and 61%, respectively). However, visible inflammation showed high sensitivity but low specificity as a marker for identifying histopathologic clearance (90% and 39%, respectively) (Table 1).

In this study, imiquimod cream, 5%, was shown to have efficacy, with clearance of LM identified in 20 of 38 patients (53% [95% CI, 36%-69%]). Efficacy was assessed after imiquimod application for 12 weeks by 2 dermatopathologists independently examining the specimen provided by excision of the entire lesion and a 5-mm margin beyond it.Quiz Ref ID An association between macroscopic clearance (removal of pigment) and histopathologic clearance was shown (P  =  .11; PPV, 65%) but this low value similarly limits its use as a clinical marker of therapeutic response. A visible inflammatory response usually occurs (sensitivity, 90%) with a successful outcome, but it cannot be depended on as an indicator of successful treatment (specificity, 39%; P  =  .04; PPV, 62%). Although discordance was noted in histopathologic assessments of 5 of 43 excision specimens, substantial agreement occurred between the 3 expert dermatopathologists ( κ  =  0.77; 95% CI, 0.57-0.96).

The best assessment method for therapeutic trials for LM is the recurrence rate found in long-term follow-up. Because standard wide-excision surgery offers as high as 90% efficacy and permits the assessment of the entire treated lesional area, it is the next best assessment method.17,20 An efficacy rate of 50% based on 10 patients followed up for a mean of 33 months (range, 11-56 months) has been recently reported.21 Two previous studies2,4 based on histopathologic assessment of the complete surgical excision specimen reported histopathologic clearance rates of 67% (4 of 6) and 75% (30 of 40) (Table 2). Quiz Ref IDTheir efficacy rates and our rate of 53% (20 of 38) are noted to be lower than those of other studies,1,3,512,2241 which used partial biopsy findings or macroscopic clearance to assess efficacy. Such assessment methods may overestimate treatment efficacy by missing persistent disease.

Table Graphic Jump LocationTable 2. Summary of Case Series Using Staged Wide Local Excision to Assess Imiquimod Treatment Efficacy

No standardized application protocol exists, to our knowledge, and our results are limited to a treatment regimen of 5 days per week for 12 weeks, which is similar to that of 9 other studies2,3,6,8,9,25,26,36,37 that used treatment duration of 12 weeks but with variable application frequencies. Our results also may be limited by surgical excision being performed at a mean of 23 (range, 1-73) days after treatment cessation because the presence of histopathologic inflammation may reduce assessment accuracy. Also, inflammation was identified in 24 of 43 excision specimens with 18 assessed as being clear of LM, 3 with residual LM, and 3 with discordant histopathologic findings. The timing of surgical excision after treatment in our study was comparable with the timing in the 2 studies2,4 that used the same assessment method, with surgical excisions performed at 2 and 8 weeks after treatment, respectively (Table 2).

The 2 independent dermatopathologic assessments for each specimen used in this study were undertaken to address the known difficulties with histopathologic assessment of LM, including the interpretation of the known reactive increase in melanocytes in proximity to surgical scars and in sun-damaged skin.42 Although it has been argued that there is a risk of missing minor residual changes if reliance is placed on hematoxylin-eosin stains only without additional immunohistochemical stains, the use of melan-A has been shown to contribute to errors in the diagnosis of melanocytic lesions in sun-damaged skin tumors.43,44 Therefore, immunostaining was not relied on for diagnosis of LM in this study. Partial biopsy of lesions compounds these difficulties. Patients with pretreatment discordant histopathologic findings were not entered into this study, and discordant histopathologic findings occurred only in 5 posttreatment specimens (discarded from analysis), so the overall concordance was high.

Quiz Ref IDImiquimod cream, 5%, used 5 days a week for 12 weeks as monotherapy, has lower efficacy in treating LM than surgical excision but may be comparable with that of other nonsurgical options for treatment of LM, including radiotherapy, cryotherapy, and carbon dioxide laser, with reported 5-year recurrence rates of 13.2%, 34.3%, and 42.2%, respectively.45 Although a visible inflammatory response usually is associated with treatment success, the inflammatory response and apparent macroscopic clearance were not reliable means of assessing therapeutic success. Quiz Ref IDImiquimod could be used as an adjunct field treatment before or after surgical excision to decrease recurrence rates and also may have a role in the management of LM when surgery is contraindicated. Close follow-up of patients with LM treated with this modality only is strongly recommended.

Correspondence: Lena Ly, MBBS, Victorian Melanoma Service, Level 1, Alfred Center, Alfred Health, Commercial Road, Melbourne, Victoria, Australia 3004 (lenaly21@yahoo.com.au).

Accepted for Publication: February 14, 2011.

Author Contributions: Dr Haskett had full access to all the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kelly, Sutton, Byrne, Curr, and Haskett. Acquisition of data: Ly, Kelly, O ’Keefe, Sutton, Byrne, Curr, Chamberlain, and Haskett. Analysis and interpretation of data: Ly, Kelly, Dowling, Swain, Wolfe, Chamberlain, and Haskett. Drafting of the manuscript: Ly, Kelly, Swain, Wolfe, Chamberlain, and Haskett. Critical revision of the manuscript for important intellectual content: Ly, Kelly, O ’Keefe, Sutton, Dowling, Swain, Byrne, Curr, Wolfe, Chamberlain, and Haskett. Statistical analysis: Wolfe. Obtained funding: Sutton and Haskett. Administrative, technical, and material support: Ly, Kelly, Sutton, Byrne, Curr, and Haskett. Study supervision: Kelly, Chamberlain, and Haskett.

Financial Disclosure: Dr Haskett received an honorarium for attendance at the 3M Pharmaceuticals Australian Aldara Advisory Board meetings for 18 months from January 1, 2005, through June 30, 2006.

Funding/Support: This study was supported in part by a research grant from the Skin and Cancer Foundation (Dr Sutton). 3M Pharmaceuticals and its successor iNova Pharmaceuticals Pty, Ltd, donated the Nikon 4500 COOLPIX S9 camera and the associated color printer for clinical photography and the Heine Delta 20 dermatoscope (Heine Optoteknic, Herrsching, Germany); they also supplied all the imiquimod cream.

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.

Previous Presentations: A version of this article was presented at the 43rd Annual Scientific Meeting of the Australasian College of Dermatologists; May 16, 2010; Darwin, Australia; and at the 7th Annual International Melanoma Congress; November 4, 2010; Sydney, Australia.

Additional Information: We are indebted to the Departments of Plastic Surgery and Anatomical Pathology at Alfred Health for supporting this study.

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Figures

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Figure 1. Schematic study flowchart.

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Figure 2. Anatomical distribution of the 43 lesions treated. Numbers indicate numbers of patients.

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Figure 3. Representative photographs of the results of treatment of lentigo maligna (LM) with imiquimod cream, 5%. A, Clinical appearance before treatment (left cheek). B, After treatment, complete macroscopic clearance without histopathologic clearance. C, Clinical appearance before treatment (left temple). D, After treatment, incomplete macroscopic clearance (residual pigment) with histopathologic clearance (evidence of histopathologic pigment incontinence). E, Clinical appearance before treatment (right cheek). F, At the end of treatment at week 12, strong visible inflammation without histopathologic clearance.

Tables

Table Graphic Jump LocationTable 1. Inflammation and Clearance in 38 Patients Treated With Imiquimod Cream, 5%
Table Graphic Jump LocationTable 2. Summary of Case Series Using Staged Wide Local Excision to Assess Imiquimod Treatment Efficacy

References

Buettiker UV, Yawalkar NY, Braathen LR, Hunger RE. Imiquimod treatment of lentigo maligna: an open-label study of 34 primary lesions in 32 patients.  Arch Dermatol. 2008;144(7):943-945
PubMed   |  Link to Article
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PubMed   |  Link to Article
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