In a study conducted in veterans who had a history of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), patients who used a cream containing 5% fluorouracil (5-FU) (multiple brands) on their face and ears twice daily for 2 to 4 weeks subsequently underwent substantially less surgery for SCC than a similar group of patients who used a control cream.
The need for surgery was reduced by 75% over the year after treatment, researchers report in a study published online January 3 in JAMA Dermatology.
Topical 5-FU has been on the market for many years. It is used in the treatment of actinic keratosis, which is a precursor of SCC, explained lead author Martin Weinstock, MD, professor of dermatology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, in an interview posted on JAMA Dermatologyalong with the study.
"We wanted to see whether it might be effective for preventing keratinocyte carcinoma, be it basal or squamous cell carcinoma," added Dr Weinstock, who is also chief of dermatology at the Providence Veterans Affairs Medical Center in Providence.
"We found that patients who were randomized to receive the 5-FU cream were substantially less likely to develop a new SCC on the area to which the cream was applied, namely, the face and ears, over the first year," he added.
This strongly suggests that 5-FU may have a role as an active chemopreventive agent in clinical practice in patients at very high risk for SCC. Dr Martin Weinstock
"So this strongly suggests that 5-FU may have a role as an active chemopreventive agent in clinical practice in patients at very high risk for SCC," Dr Weinstock observed.
Details of the Study
The Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) trial randomly allocated 932 participants (median age, 70 years) to receive either the 5-FU cream or a control cream. Both creams were applied twice a day to the patients' face and ears for 2 to 4 weeks.
All participants had a history of at least three keratinocyte carcinomas during the past 5 years. Almost all the patients were white men.
The population was specifically chosen because veterans are exposed to a substantial amount of sunlight during and after their military service and are thus likely to have a history of keratinocyte carcinomas or are at high risk of developing them.
Indeed, during the 5 years before enrolling in the study, 93% of participants had had at least one BCC; 44% had developed at least three BCCs; 39% had developed at least one invasive SCC; and 18% had developed at least one SCC in situ.
All participants also received a suncreen of sun protection factor 30 and were counseled on its use.
"Study end points were surgically treated BCC or SCC on the face and ears," the authors note.
Patients were followed for 4 years; the median follow-up was 2.8 years.
During the full 4-year study, "there was no difference between treatment groups in time to first keratinocyte, basal cell, or squamous cell carcinoma," the researchers report.
On the other hand, during the first year following short-term use of the 5-FU cream, only 1% of participants in the active treatment group developed an SCC, compared to 4% in the control group.
This translated into a 75% reduction in the need to treat SCCs surgically between the two treatment groups (P = .002), the researchers note.
For BCC, the 5-FU cream reduced future risk by 11% during the first year, but this was not statistically significant relative to controls, the authors point out.
The investigators also assessed the risk of participants requiring treatment with Mohs surgery for either BCC or SCC during the study period. They point out that Mohs surgery is the most resource-intensive and therefore expensive of the treatments used for BCC and SCC and was the most common modality used for the treatment of keratinocyte carcinomas among study participants.
Using Mohs surgery as an end point, the investigators documented a 49% reduction in the number of participants who received Mohs surgery for BCCs and keratinocyte carcinomas in the 5-FU group compared with controls, at least during the first year following application of the active cream.
Table. Keratinocyte Carcinomas (KCs) Treated With Mohs Surgery Over the Trial
| Period | 5-FU | Control Cream | Relative Risk Reduction |
|---|---|---|---|
| KCs Treated With Mohs Surgery | |||
| Year 1 | 20 | 41 | 0.72 |
| Overall study period | 153 | 149 | 1.07 |
| Participants With ≥1 KCs Treated With Mohs Surgery | |||
| Year 1 | 16 | 31 | 0.51 |
| Overall study period | 101 | 92 | 1.09 |
| BCCs Treated With Mohs Surgery | |||
| Year 1 | 17 | 36 | 0.56 |
| Overall study period | 120 | 118 | 1.04 |
| Participants With ≥1 BCCs Treated With Mohs Surgery | |||
| Year 1 | 14 | 27 | 0.51 |
| Overall study period | 87 | 79 | 1.09 |
The 5-FU cream is associated with some adverse effects (AEs), including erythema, which occurred in more than 90% of the participants in the active treatment group.
Twenty-one percent of participants in the active treatment arm also rated the AEs they experienced as "severe" 6 months after starting treatment; 40% of them rated the AEs as "moderate."
In contrast, more than three quarters of control patients reported no AEs at the 6-month assessment point.
On the other hand, 87% of veterans who received the 5-FU cream indicated they would be willing to treat themselves again if the cream was proven to reduce future skin cancers.
Indeed, the investigators suggest that given the waning effectiveness of the cream in protecting patients against future SCCs after 1 year, it would be "reasonable" to consider repeat treatment every year to reduce the need for Mohs surgery for recurrent SCCs in high-risk populations.
If we could take a big chunk out of the incidence of SCC, it would be a major public health benefit. Dr Martin Weinstock
"Squamous cell carcinomas are very, very common, so if we could take a big chunk out of the incidence of SCC, it would be a major public health benefit," Dr Weinstock concluded.
Asked by Medscape Medical News to comment on the study, David Leffell, MD, David Paige Smith Professor of Dermatology and Surgery, Yale School of Medicine, New Haven, Connecticut, pointed out that it is well known that 5-FU reduces the incidence of actinic keratoses, which are considered precursors to SCC, so "it is not surprising that there would be no effect on basal cell cancer," he said in an email.
"The real purpose of the study was to see if the use of a relatively inexpensive topical agent could reduce the number of cases of SCC that require Mohs surgery," Dr Leffell emphasized.
The fact that this cream did reduce the need for Mohs surgery in participants may be slightly confounded by the fact that the decision to use Mohs surgery to treat SCC always depends on the judgment of the referring physicians, so a reduction in this end point may not be as cut and dry as it might first appear, Dr Leffell suggested.
"In practice, repeat courses of 5-FU are needed to manage people with multiple actinic keratoses," Dr Leffell pointed out. He indicated that repeat courses of 5-FU may be needed to manage SCC as well.
"However, if the study findings are real, this approach could become a standard in the population at risk," Dr Leffell said.
The study was supported in part by the Cooperative Studies Program of the Office of Research and Development, US Department of Veterans Affairs. Dr Weinstock is employed by Brown Dermatology, Inc (Brown University Department of Dermatology's faculty practice) and has served as a consultant to AbbVie, Castle, and Celgene.
JAMA Dermatol. Published online January 3, 2018. Full text
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