A Non-Surgical and Cost-Effective Treatment Approach Employing Topical Imiquimod, 5-Fluorouracil, and Tretinoin for Primary Non-Melanoma Skin Cancers

March 2021 | Volume 20 | Issue 3 | Original Article | 260 | Copyright © March 2021

Published online January 28, 2021

William J. Nahm BAa,b, John Shen MDc, Patrick M. Zito DO PharmDb,d, Adrianna M. Gonzalez MDb,e, Nicole Nagrani MDb,f, Kevin Moore MD MPHb,g, Evangelos V. Badiavas MD PhDb, Robert S. Kirsner MD PhDb,h, Anna J. Nichols MD PhDb,h

aNew York University Grossman School of Medicine, New York, NY
bDr. Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL
cShen Dermatology, Temecula, CA
dLarkin Community Hospital, Palm Springs, Hialeah, FL
eJohn T. Mather Hospital, Port Jefferson, NY
fBrandon Regional Hospital, Brandon, FL
gHarvard Combined Dermatology Residency Program, Harvard Medical School, Boston, MA
hSylvester Comprehensive Cancer Center, Miami, FL

Background: Minimally invasive alternative approaches to treat non-melanoma skin cancers remain limited and unproven.
Objective: We aim to assess the efficacy of varying combinations of anti-tumor agents—imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream—with brief cryotherapy in treating non-melanoma skin cancers.
Methods: This retrospective study included 690 cases of non-melanoma skin cancers in 480 patients who received a diagnosis of a basal cell carcinoma or squamous cell carcinoma during a ten-year period. During treatment period, patients applied 30 applications of one of three combinations (imiquimod/tretinoin, 5-fluorouracil/tretinoin, or imiquimod/5-fluorouracil/tretinoin) and had cryotherapy every 2 weeks. Each patient had a clinical examination at least three years post-treatment or documented treatment failure. Clearance was defined by a lack of persistence or recurrence for 3 years following the completion of treatment. The likelihood of lesion clearance was evaluated using multivariable logistic regression analysis.
Results: A total of 186 cases (97; basal cell carcinoma and 89; squamous cell carcinoma) in 133 patients [37% women and 63% men; median (interquartile range) age, 77 (69, 83) years] met the inclusion criteria. Multivariable logistic regression analysis adjusting for clinical and lesion variables demonstrated that, relative to the imiquimod/5-fluorouracil/tretinoin treatment approach, imiquimod/ tretinoin (odds ratio, 0.05; 95% confidence interval, 0.00-0.99) and 5-fluorouracil/tretinoin (0.02; 0.00–0.45) were associated with lower likelihoods of lesion clearance. Likewise, morpheaform basal cell carcinoma had a lower probability of clearance (0.05; 0.00–0.72).
Conclusions: The combination of imiquimod/5-fluorouracil/tretinoin with cryotherapy had high clearance rates and was the most effective treatment regimen.

J Drugs Dermatol. 20(3):260-267. doi:10.36849/JDD.2021.5427


Non-melanoma skin cancers (NMSCs), predominately comprised of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are the most common malignancies, affecting around 5.4 million people a year in the United States (US).1,2 The incidence of NMSCs continues to rise with estimates suggesting over 2 million and 1 million new cases of BCC and SCC, respectively, in the US each year.3-5 From 2000 to 2010, the BCC incidence rose 145% and SCC incidence rose 263%.4,6 Similar, but less dramatic, rises were seen worldwide.7

The annual expenditure to treat NMSCs is increasing more rapidly than those to treat any other cancers, with average costs approaching $4.8 billion per year in the US. This number highlights the considerable health and economic burden of these malignancies.8 Surgical excision including Mohs micrographic surgery (MMS) remain the standard for the treatment of NMSCs.9,10 However, surgical approaches are associated with direct high financial costs, indirect costs such as lost work productivity, complications such as infections, and potentially poor cosmetic outcomes. Other treatment options