Original article
A quantitative systematic review of the efficacy of imiquimod monotherapy for lentigo maligna and an analysis of factors that affect tumor clearance

https://doi.org/10.1016/j.jaad.2015.05.022Get rights and content

Background

The reported efficacy of imiquimod for lentigo maligna varies widely, without consensus on tumor or treatment factors that can impact tumor clearance.

Objective

We sought to provide a more precise estimate of clearance rates in patients with lentigo maligna who are treated with imiquimod and to analyze factors that can impact tumor clearance.

Methods

We performed a literature search for biopsy-proven lentigo maligna treated with imiquimod monotherapy, linked treatment and outcome data to individual tumors, calculated histologic and clinical clearance rates with 95% confidence intervals (CIs), and analyzed the impact of tumor and treatment factors on tumor clearance using logistic regression.

Results

Based on 347 tumors from 45 studies, histologic and clinical clearance rates were 76.2% (95% CI, 71.4-81.0%) and 78.3% (95% CI, 73.6-82.9%), respectively. The incidence of clinical recurrence was 2.3% (95% CI, 0.5-4.2%), with a mean follow-up of 34.2 ± 11.8 months. Treatment with >60 total applications, or with >5 applications per week was associated with a higher likelihood of histologic clearance (odds ratio, 8.4 [95% CI, 2.9-24.1] and odds ratio, 6.0 [95% CI, 2.4-14.7], respectively).

Limitations

Our limitations included the accuracy and scope of published data, variable follow-up times, potential patient selection, and publication bias related to case series/cohort designs of previous studies.

Conclusion

Imiquimod offers a 76% histologic and 78% clinical clearance rate for lentigo maligna. Both cumulative dose and treatment intensity affect tumor clearance.

Section snippets

Data collection

PubMed search parameters were restricted to studies published in English between 2000 and 2014 containing the following terms: “Aldara,” “imiquimod,” “lentigo maligna,” and “melanoma in situ.” These studies were independently reviewed by Ms Mora and Dr Nguyen. Differences in study interpretation were discussed among all 3 authors to reach a consensus. All included cases were treated with imiquimod 5% cream. Tumors were excluded if (1) the diagnosis of LM was equivocal (ie, there was discordance

Results

Our PubMed search yielded 85 studies, of which 45 met the inclusion criteria (Table I). The most common reason for exclusion was the use of combination therapy of imiquimod with topical tazarotene, laser, or cryotherapy. Some tumors in original studies were not included in the final analysis because of the use of combination therapy (1),40 because they had been previously published (1),26 because they had a diagnosis other than LM (1),44 or because there were dropouts (2).18, 55 The cases

Discussion

Imiquimod offers reasonable histologic and clinical clearance rates for both primary and recurrent/previously treated LM, with a cumulative dose of >60 applications and treatment intensity of >5 applications per week predicting a higher likelihood of tumor clearance. Based on tumor-level analysis of 347 tumors from 45 published studies, the clinical and histologic clearance rates were 78.3% (95% CI, 73.6-82.9%) and 76.2% (95% CI, 71.4-81.0%), respectively. Treatment protocols varied

References (61)

  • I. Alarcon et al.

    In vivo reflectance confocal microscopy to monitor the response of lentigo maligna to imiquimod

    J Am Acad Dermatol

    (2014)
  • R.W. Tsang et al.

    Lentigo maligna of the head and neck. Results of treatment by radiotherapy

    Arch Dermatol

    (1994)
  • C. Erickson et al.

    Treatment options in melanoma in situ: topical and radiation therapy, excision and Mohs surgery

    Int J Dermatol

    (2010)
  • M. Haedersdal

    Cutaneous side effects from laser treatment of the skin: skin cancer, scars, wounds, pigmentary changes, and purpura–use of pulsed dye laser, copper vapor laser, and argon laser

    Acta Derm Venerol Suppl

    (1999)
  • S.R. Rheingold et al.

    Therapy-related secondary cancers

  • M. Naylor

    Changes in skin cancer management

    J Clin Aesthet Dermatol

    (2010)
  • T. Desai et al.

    Basic pharmacology of topical imiquimod, 5-fluorouracil, and diclofenac for the dermatologic surgeon

    Dermatol Surg

    (2012)
  • M.P. Schön

    Imiquimod: mode of action

    Br J Dermatol

    (2007)
  • National Cancer Institute website. FDA approval for imiquimod. Available at:...
  • I. Ahmed et al.

    Imiquimod: a novel treatment for lentigo maligna

    Br J Dermatol

    (2000)
  • U. Borucki et al.

    Topical treatment of lentigo maligna melanoma with imiquimod 5% cream

    Dermatology

    (2003)
  • M.S. Chapman et al.

    Histologic resolution of melanoma in situ (lentigo maligna) with 5% imiquimod cream

    Arch Dermatol

    (2003)
  • E. Epstein

    Extensive lentigo maligna clearing with topical imiquimod

    Arch Dermatol

    (2003)
  • M.A. Hyde et al.

    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

    Arch Dermatol

    (2012)
  • S.F. Rajpar et al.

    Imiquimod in the treatment of lentigo maligna

    Br J Dermatol

    (2006)
  • G.H. Fisher et al.

    Treatment of melanoma in situ on sun-damaged skin with topical 5% imiquimod cream complicated by the development of invasive disease

    Arch Dermatol

    (2003)
  • M.F. Naylor et al.

    Treatment of lentigo maligna with topical imiquimod

    Br J Dermatol

    (2003)
  • C.J. Fleming et al.

    A pilot study of treatment of lentigo maligna with 5% imiquimod cream

    Br J Dermatol

    (2004)
  • P. Michalopoulos et al.

    Characterization of the cellular infiltrate during successful topical treatment of lentigo maligna with imiquimod

    Br J Dermatol

    (2004)
  • C.M. Munoz et al.

    Successful treatment of persistent melanoma in situ with 5% imiquimod cream

    Dermatol Surg

    (2004)
  • Cited by (62)

    • Targeted Therapy and Immunotherapy in Melanoma

      2023, Dermatologic Clinics
      Citation Excerpt :

      Trials combining T-VEC with ipilimumab have also shown promising results and other combinations are under investigation.61,62 In addition, other intralesional agents such as interleukin-2 and topical agents such as imiquimod and diphencyprone have been utilized with varying degrees of success; their role in the management of melanoma remains unclear (see Table 2).63–66 Even though immunotherapy and targeted therapy have shown significant benefits in the treatment of melanoma, a number of tumors either fail to respond or eventually progress despite these treatments.

    • Change in lentigo maligna score assessed by in vivo reflectance confocal microscopy after 1 month of imiquimod treatment for lentigo maligna management

      2022, Journal of the American Academy of Dermatology
      Citation Excerpt :

      In previous studies, the clearance rate varied from 60 to 100%.34,35 Several hypotheses have been proposed to explain this variability of the clinical response to imiquimod.36,37 The first hypothesis is based on a nonstandardization of the treatment regimens.

    • Lentigo Maligna

      2021, Clinics in Plastic Surgery
    View all citing articles on Scopus

    Funding sources: None.

    Conflicts of interest: None declared.

    View full text