Sunscreen may not be the only ointment that helps prevent skin cancer. A cream that combines 5-fluorouracil (5-FU) and a synthetic form of vitamin D has been shown to reduce the risk that precancerous skin lesions will progress to squamous cell carcinoma (SCC), the second most common form of skin cancer.

A couple of years ago, the combination cream was evaluated as a means of eliminating actinic keratoses, precancerous lesions that emerge in sun-damaged skin. Although the chance of an individual lesion progressing to cancer is only 1%, most SCCs develop from existing actinic keratosis lesions.

The combination cream did indeed reduce the number and size of actinic keratosis lesions. Interested in determining whether the combination cream also reduced the risk of SCC, scientists based at Massachusetts General Hospital and the Washington School of Medicine followed up on the original study. They found that the risk of SCC development on the face and scalp was reduced by almost 75%.

Details of the new research appeared March 21 in JCI Insight, in an article titled, “Skin cancer precursor immunotherapy for squamous cell carcinoma prevention.” According to this article, a short course of 5-FU plus calcipotriol treatment on the face and scalp is associated with induction of robust T cell immunity and tissue-resident memory T (Trm) cell formation against actinic keratosis.

Standard therapy for actinic keratoses is topical 5-FU alone. Calcipotriol is a standard therapy for psoriasis, an autoimmune disorder that causes red, scaly patches of skin. Apparently, calcipotriol also activates the immune system’s T cells, which then attack the tumor cells.

“This finding provides the first clinical proof-of-concept that an immunotherapy directed against premalignant tumors can prevent cancer,” said the study’s senior author Shawn Demehri, MD, PhD, an associate professor of dermatology at Massachusetts General Hospital and Harvard Medical School. “We hope our findings will establish that the use of premalignant lesions as personalized therapeutic targets can train the immune system to fight against the progression to cancer.”

Of the 130 participants in original trial—64 who received calcipotriol plus 5-FU and 66 who received a control treatment of 5-FU in petroleum jelly—three-year outcome results were available for 84 individuals, 39 who received the combination treatment, and 45 who received the control treatment. Results for treatment on the face and scalp were available for 72 participants (32 combination treatment and 40 controls).

Overall, a greater proportion of participants who received the combination treatment for lesions on their face and scalp remained free of SCC development for more than three years after treatment, with only 7% developing SCC compared with 28% in the control group. Samples of treated face and scalp tissues of 22 participants showed higher levels of tissue-resident memory T cells—both CD4+ and CD8+ T cells—in normal skin treated with the combination treatment, compared with the control group.

While treatment did not reduce SCC development on the arms, the investigators believe that may result from greater immune system activation on the face and scalp along with better penetration of topical treatments on those areas. They hypothesize that longer treatment with calcipotriol plus 5-FU may be required to reduce SCC risk on the arms and other parts of the body.

“Our study establishes calcipotriol plus 5-FU combination as a short, well-tolerated topical treatment with the potential to reduce the incidence of SCC, therefore addressing a major public health problem,” the article’s authors concluded. “These remarkable findings substantiate the use of immunotherapeutic agents with minimal side effects and high efficacy against precancerous lesions in order to reduce the risk of cancer development and recurrence, which may be broadly applicable to skin and internal malignancies.”

“Further studies are warranted to determine the optimal calcipotriol plus 5-FU treatment duration required to induce a chemopreventive effect at all anatomical sites at risk for SCC development,” the authors indicated. “In addition, longer follow-up is required to determine whether the chemopreventive effect of calcipotriol plus 5-FU treatment extends beyond three years. Finally, it will be critical to examine the efficacy of calcipotriol plus 5-FU immunotherapy for skin cancer prevention in high-risk populations including organ transplant recipients.”

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