Can This Topical Cream Prevent Nonmelanoma Skin Cancer?

Prevention of Nonmelanoma Skin Cancers

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), grouped together as keratinocyte carcinomas (KCs), are the most common skin cancers, with more than 5 million diagnosed in the United States in 2012.^[1] Although less aggressive than malignant melanoma and Merkel cell carcinoma, KCs comprise more than 75% of skin cancers and cause significant morbidity and billions of dollars annually in treatment expenses.^[2] KC risk factors include Fitzpatrick I-II skin phototype, a history of heavy sun exposure, blistering sunburns, family history of KC, and immunosuppression.^[3]

Photoprotection (protective clothing, avoidance of peak sun exposure, sunscreen application) remains the cornerstone of KC prevention. Topical retinoids, low-dose oral retinoids, and nicotinamide yield modest protection against KC in high-risk individuals but require continuous therapy.^[4,5,6] In contrast, topical fluorouracil chemotherapy is highly effective at treating actinic keratoses (precursor lesions of SCC), superficial BCCs, and—off—label-SCC in situ^[7] but has no established role in preventing KC.

Role of Topical Fluorouracil

To test whether topical fluorouracil could reduce the number of KCs requiring surgical treatment over a 4-year period, Weinstock and colleagues^[8] enrolled 932 Veterans Affairs patients (98% men; 99% white; median age, 70 years); these volunteers were randomly assigned to apply either topical fluorouracil, 5% (n = 468) or placebo vehicle cream (n = 464) to the face and ears twice daily for 2-4 weeks. Patients with higher KC risk due to immunosuppressive therapy or genetic syndromes were excluded from the trial.

Clinical outcome measures included the following:

• The number of facial and ear primary KCs (total number, BCCs, SCCs) requiring surgical treatment during the first year after pulse treatment and after 4 years;

• Time to first surgically treated KC, BCC, and SCC; and

• Tolerability and adverse effects of topical fluorouracil versus placebo.

The study's findings were the following:

1. Over the 4-year study period, there was no reduction in the number of KCs, BCCs, or SCCs. There was also no difference in time to first KC, BCC, or SCC.

2. There was no reduction in the number of BCCs during the first year.

3. During the first year after treatment, fewer patients developed SCCs in the fluorouracil (n = 5; 1%) versus placebo (n = 20; 4%) groups. This represents a 75% reduction in the risk for SCC requiring surgery—albeit for the first year only.

4. Topical fluorouracil pulse treatment was also associated with a reduction in all KCs treated with Mohs surgery over the 4-year follow-up period.

5. Topical fluorouracil caused the expected side effects of erythema, crusting, and irritation; however, 87% of study participants said that they would repeat this treatment if it reduced future KC risk.

Viewpoint

This randomized trial showed a significant but temporary reduction in the number of SCCs requiring surgical intervention following a single 2- to 4-week pulse of topical fluorouracil cream, 5%. In contrast, topical fluorouracil did not reduce the incidence of BCCs, even during the first year after application.

Of note, the chemoprotective effect of topical fluorouracil seems to be short-lived; there was no observed reduction in the incidence of KCs, BCCs, or SCCs over a 4-year follow-up period. Whether additional pulses of topical fluorouracil can extend the observed chemoprotective effect remains to be seen. Furthermore, the study was not designed to assess any potential survival benefit from topical fluorouracil chemotherapy. It would also be interesting to know whether KCs in the treatment versus placebo groups showed less aggressive histopathology or required less aggressive intervention.

Because most patients at higher risk for KC will have a background of actinic keratoses (AKs), periodic "field" treatment with topical fluorouracil is beneficial, independent of the above observations. Alternative topical AK treatments such as photodynamic therapy (with aminolevulinic acid), imiquimod, ingenol mebutate, and diclofenac^[7] may also reduce the incidence of KCs. Hence, future studies should address whether any of these alternatives yield similar or superior results.