Before OR After: Is There a Connection Between the Use of Adjunctive Nonmelanoma Skin Cancer Treatments and Subsequent Invasive Tumors?
May 2015 | Volume 14 | Issue 5 | Editorials | 450 | Copyright © May 2015
Emily Stamell Ruiz MD,a Joel L. Cohen MD,b,c
and Adam Friedman MDd
aDepartment of Der matology, Brigham & Women’s Hospital, Boston, MA
bAboutSkin Dermatology and Der mSurgery, Englewood, CO
cDepartment of Der matology, University of Colorado, Denver, CO
dDivision of Der matology, Department of Medicine, and Department of
Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY
fluorouracil cream), Fluoroplex® (1% fluorouracil cream),
and Carac® (0.5% fluorouracil cream). Topical fluorouracil is
FDA-approved for the treatment of AKs (Efudex, Carac, and
Fluoroplex) and superficial BCCs (Efudex). Sustained clearance
at 12 months ranges from 33%12 to 81.1%.9 Although
not FDA-approved for the treatment of squamous cell carcinoma
in situ, 5% fluoruracil cream has been shown to be
efficacious.13,14 However, despite approval since the 1970’s, the
Veterans Affairs Topical Tretinoin Chemoprevention trial noted
that prior treatment with topical fluorouracil was associated
with a higher risk of development of morpheaform BCCs. These
authors concede that fluorouracil may have destroyed superficial
cancer cells while leaving deeper pockets untouched.
However, they open the door to a causal relationship between
therapy and these tumors by stating that “fluorouracil treatment
may predispose to development of morpheaform BCC.”3
As presented above, these 3 recent reports suggest that the
topical therapies may be associated with future development of
histologically more aggressive BCCs. However, it is important to
recognize that each modality is only indicated for the treatment
of superficial neoplastic tumors. More aggressive tumor subtypes
may be deeper than clinically apparent, making treatment
beyond reach. This concept was clearly illustrated in a case series
by Sambandan and Goldman5 in which they presented 8 patients
initially treated for AKs who failed to improve with destructive
modalities. Upon biopsy the lesions were noted to have underlying
BCCs. Although there is a possibility that the BCC developed
in response to the destructive modality, it is more likely that the
tumor was always present but not clinically apparent.
In this context, it is important to recognize that the findings
of histologically aggressive tumors in these 3 studies may be
due to their lack of response to the PDT, imiquimod, or fluoruracil,
and not to the therapy itself. Furthermore, the 3 studies
provide weak evidence supporting their causal relationship in
causing aggressive skin cancers. These therapeutics play an
important role in the treatment of NMSC, but they do have
their limitations. In addition to thorough clinical examinations,
other imaging modalities such as high-frequency ultrasound
may be useful in identifying deeper tumors.15 Close clinical
follow up after topical field therapy is prudent in order to not
miss deeper, aggressive tumors.
Dr. Cohen has served as a consultant for Valeant and DUSA.
- Rogers HW, Weinstock MA, Harris AR, et al. Incidence estimate of nonmelanoma
skin cancer in the United States, 2006. Arch Dermatol. 2010;146(3):283-287.
- Fiechter S, Skaria A, Nievergelt H, Anex R, Borradori L, Parmentier L. Facial
basal cell carcinomas recurring after photodynamic therapy: a retrospective
analysis of histological subtypes. Dermatology. 2012;224(4):346-351.
- Xiong MY, Korgavkar K, Digiovanna JJ, Weinstock MA; Veterans Affairs
Topical Tretinoin Chemoprevention Trial Group. Fluorouracil and other predictors
of morpheaform basal cell carcinoma among high-risk patients: the
Veterans Affairs Topical Tretinoin Chemoprevention Trial. JAMA Dermatol. 2014;150(3):332-334.
- Skaria AM. Facial basal cell carcinomas recurring after imiquimod therapy.
- Sambandan PG, Goldman GD. Infiltrative basal cell carcinomas presenting
as actinic keratosis: implications for clinical practice. Dermatol Surg.
- De Rosa FS, Bentley MV. Photodynamic therapy of skin cancers: sensitizers,
clinical studies and future directives. Pharm Res. 2000;17(12):1447-1455.
- Braathen LR, Szeimies RM, Basset-Seguin N, et al. Guidelines on the use
of photodynamic therapy for nonmelanoma skin cancer: an international
consensus. International Society for Photodynamic Therapy in Dermatology,2005. J Am Acad Dermatol.
- Ko DY, Kim KH, Song KH. Comparative study of photodynamic therapy with
topical methyl aminolevulinate versus 5-aminolevulinic acid for facial actinic
keratosis with long-term follow-up. Ann Dermatol. 2014;26(3):321-331.
- Lecluse LL, Spuls PI. Photodynamic therapy versus topical imiquimod versus
topical fluorouracil for treatment of superficial basal-cell carcinoma: a
single blind, non-inferiority, randomised controlled trial: a critical appraisal. Br
J Dermatol. 2015;172(1):8-10.
- Desai T, Chen CL, Desai A, Kirby W. Basic pharmacology of topical imiquimod,
5-fluorouracil, and diclofenac for the dermatologic surgeon. Dermatol
- Stockfleth E, Christophers E, Benninghoff B, Sterry W. Low incidence of new
actinic keratoses after topical 5% imiquimod cream treatment: a long-term
follow-up study. Arch Dermatol. 2004;140(12):1542.
- Krawtchenko N, Roewert-Huber J, Ulrich M, Mann I, Sterry W, Stockfleth E.
A randomised study of topical 5% imiquimod vs. topical 5-fluorouracil vs.
cryosurgery in immunocompetent patients with actinic keratoses: a comparison
of clinical and histological outcomes including 1-year follow-up. Br J
Dermatol. 2007;157(suppl 2):s34-s40.
- Welch ML, Grabski WJ, McCollough ML, et al. 5-fluorouracil iontophoretic
therapy for Bowen’s disease. J Am Acad Dermatol. 1997;36(6 pt 1):956-958.
- McGillis ST, Fein H. Topical treatment strategies for non-melanoma skin cancer
and precursor lesions. Semin Cutan Med Surg. 2004;23(3):174-183.
- Desai TD, Desai AD, Horowitz DC, Kartono F, Wahl T. The use of high-frequency
ultrasound in the evaluation of superficial and nodular basal cell carcinomas.
Dermatol Surg. 2007;33(10):1220-1227.