Combination treatment with topical calcipotriol plus 5-fluorouracil (5-FU), often used as a treatment for actinic keratosis (AK), appears to also reduce the chance that the treated skin will develop squamous cell carcinomas (SCCs), according to findings published online in JCI Insight (March 21, 2019).
“This finding provides the first clinical proof-of-concept that an immunotherapy directed against premalignant tumors can prevent cancer,” says Dr. Shawn Demehri, senior author of the report, in a press release.
“We hope our findings will establish that the use of premalignant lesions as personalized therapeutic targets can train the immune system against the progression to cancer.”
Precancerous actinic keratosis cells – blue cells in boxed area at surface of skin – under attack by T cells (pink) induced by treatment with calcipotriol plus 5-FU, which appeared to reduce the risk of subsequent squamous cell carcinoma development by 75 percent. Photo by: Kenneth Ngo, Massachusetts General Hospital Center for Cancer Immunology/Cutaneous Biology Research Center
Dr. Demehri is a dermatologist at the Massachusetts General Hospital Center for Cancer Immunology and the Cutaneous Biology Research Center, an assistant professor of dermatology at Harvard Medical School, and director of the hospital's High Risk Skin Cancer Clinic.
According to the release, while the chance of an individual lesion progressing to cancer is only 1%, the majority of SCCs develop from existing AK lesions.
The current study follows up on the participants of a 2017 trial, also conducted by Dr. Demehri and his colleagues, that showed twice-daily treatment for four days with a combination of calcipotriol, an approved treatment to treat psoriasis, and 5-FU cream, a treatment for AK, significantly reduced the number and size of AK lesions.
This follow-up aimed to determine whether or not the combined treatment reduced the risk of the participants developing SCCs.
Three-year outcome results were available for 84 of the 130 participants in original trial. That included 39 who received the combination treatment and 45 who relieved a control treatment of 5-FU in petrolatum. 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.
SCC development on the arms was not reduced by the combination treatment, and the authors suggest this may be due to greater immune system activation on the face and scalp, combined 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 previous findings that calcipotriol plus 5-FU is highly effective for actinic keratosis clearance has led to its being increasingly used in clinics around the world, although further clinical studies are required for formal [U.S.] FDA approval,” said Dr. Demehri. “The treatment of SCC can be costly and has significant side effects, and it can be deadly, particularly for patients with suppressed immune systems.
“The primary reason for treating actinic keratosis is to prevent SCC development, and our findings suggest this immunotherapy may be an effective way of achieving that goal,” he said. “Finding that targeting precancerous lesions with a robust T-cell-directed immunotherapy can yield effective cancer prevention may be applicable to other organs than the skin, something we hope to investigate for malignancies such as breast cancer, for which immunoprevention is an urgent, unmet need.”
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