A randomized trial of 932 veterans at high risk for keratinocyte carcinoma showed that topical fluorouracil, 5%, applied twice daily to the face and ears for up to four weeks, reduced the risk of squamous cell carcinoma (SCC) requiring surgery by 75% in the first year after use (risk ratio 0.25, P=0.002), researchers found.
Risk of basal cell carcinoma (BCC), however, was similar at about 10% in the first year in the fluorouracil group and in controls, reported Martin A. Weinstock, MD, PhD, of Providence Veterans Affairs Medical Center in Rhode Island, and colleagues online in JAMA Dermatology.
There was no difference in risk of keratinocyte carcinoma in year 1 and the risk of either SCC or BCC was not reduced over the full four-year trial period. Moreover, patients reported a high rate of severe or moderate adverse effects during treatment.
Nevertheless, most participants said they would repeat the treatment if it was shown to be conclusively effective in preventing skin cancer. These findings suggest a possible role for the annual use of topical fluorouracil chemoprevention in special high-risk populations, including patients who have received transplants, the investigators said.
In the United States, keratinocyte carcinoma accounts for about three-quarters of all cancers, and incidence is rising.
“It is reasonable at this point to consider the use of a standard and perhaps annual course of topical fluorouracil, 5%, to the face and ears for the reduction of SCC risk in high-risk populations, and potentially for a reduction in need for Mohs surgery,” Weinstock and colleagues wrote. “Topical fluorouracil is the first agent we know of that demonstrates extended post-treatment effects in SCC chemoprevention.”
No “rebound” effect of increased SCCs was observed in the fluorouracil group in year 2 or subsequently. However, the investigators did note a large 49% reduction in the number of fluorouracil group participants who had Mohs surgery treatments for BCCs and keratinocyte carcinoma compared to controls.
More study is also required to better define the effect of fluorouracil on BCC risk, including BCC that requires Mohs surgery, they said.
For the the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, participants were recruited from May 2009 through September 2011, and followed through June 2013. Almost all were male (98%) with a median age of 70 years.
Treatment and control groups were matched for demographic characteristics, military service periods, sunburn, Fitzpatrick skin type, sun protection use during the study, and medical histories, including at least two prior BCCs or SCCs.
In addition to the fluorouracil treatment, participants also received a 30 SPF sunscreen and received education about skin cancer, sunscreen, and sun safety.
Median follow-up was 2.8 years and 97% of participants in each group were followed for at least one year after randomization.
In the first year, 95 of 299 participants (32%) developed BCC and 25 of 108 participants (23%) developed SCC including five participants (1%) in the fluorouracil group and 20 (4%) in the control group.
The only difference in BCC risk was seen in year 2 of the study, the study authors report. Notably, this risk was higher in the fluorouracil group (87 versus 59 tumors; P=0.01).
There were no differences in BCC risk in years 1, 3, or 4 and the only difference in SCC risk was the significant decrease seen in year 1.
Among 27 participants in the control group, 36 underwent Mohs treatment for BCCs and 14 participants in the fluorouracil group underwent Mohs for 17 BCCs (RR 0.51, P=0.045). Five patients in the control group and three in the fluorouracil group were treated for SCCs requiring Mohs surgery.
In year 1, the RR for keratinocyte carcinoma was 0.51 (P=0.02) and there were no differences between groups over the 4-year study period.
Weinstock and colleagues acknowledged the adverse effects of fluorouracil and consequently evaluated participants’ completion of the medication course, the occurrence of adverse events, and patients’ attitudes toward using the drug in the future.
A total of 85% of fluorouracil participants (397 of 468) and 96% of controls completed at least 28 doses of the study medication. However, only 31% of those taking fluorouracil group completed 56 doses compared to 81% of controls.
After 2 weeks, 92% of participants in the fluorouracil group reported erythema, and 61% had mild-to-moderate crusting.
After six months, 21% in the fluorouracil group retrospectively rated treatment adverse effects as “severe,” 40% as “moderate,” 25% as “mild,” and 14% as “none.” At the six-month check-in, 76% of controls reported no adverse effects.
When surveyed at six and 12 months, 87% of fluorouracil group participants said they would repeat treatment if it was shown to be effective in reducing future skin cancers.
“This trial demonstrates a proactive approach that is effective,” the study authors point out. Although annual application may be needed since the effect appears to last for only a year, clinical experience indicates there may be fewer adverse effects with the second and third application, they noted. This may be due to improvement in keratinocytic dysplasia following application to sun-damaged areas.
More study is needed to more precisely define the groups that would most benefit, they added.
A randomized study has shown that daily ingestion of a large dose of nicotinamide (NNA) can reduce the risk of SCC and BCC by 23%. However, this beneficial effect disappears as soon as dosing stops, Weinstock and colleagues said. Notably, the results indicated that nicotinamide may simultaneously increase the risk of the most aggressive types of BCC and SCC.
Study limitations include the potential unblinding of participants (but not investigators) due to the adverse effects of treatment as well as potential limited generalizability to women and younger individuals.
This study was supported by the U.S. Department of Veterans Affairs. Lead study author Weinstock reported relationships with AbbVie, Castle, and Celgene. One co-author reported a relationship with Pfizer. Other study authors declared they had no potential conflicts of interest.