Addition of calcipotriene to 5-FU increases efficacy, tolerability as AK treatment

 

A combined formulation of calcipotriol and 5-fluorouracil (5-FU) outperformed 5-FU alone in reducing the number of actinic keratoses (AKs), with a shorter treatment course and less inflammation than typically seen with 5-FU alone, researchers reported in a study published online in November.

5-FU is effective, but it produces crusting and significant irritation, and is temporarily disfiguring, creating discomfort and inconvenience that often leads to poor patient compliance with treatment.

Robert Boston

In light of recent developments surrounding tumor immunotherapy, the researchers decided to combine 5-FU with calcipotriol (calcipotriene, which is approved for psoriasis), which induces thymic stromal lymphopoietin (TSLP), “an epithelium-derived cytokine and a master regulator of allergic inflammation in the skin,” according to the authors. TSLP in turn recruits anti-tumor T cells.

After demonstrating that the combined treatment reduces AKs in mice, they conducted the study of 131 patients with AKs, randomized to treatment with a cream containing 5% 5-FU and 0.005% calcipotriol, or Vaseline plus 5% 5-FU alone. Participants applied the treatments twice per day for 4 days.

Eight weeks after treatment, the combination group had a mean 87.8% reduction in the number of AKs on the face, compared with 26.3% of the 5-FU controls. The treatment group also had better responses on the scalp (a mean 76.4% reduction in AKs versus 5.7%), right upper extremity (68.8% versus 9.6%), and left upper extremity (79% versus 16.3%). All differences were statistically significant (P less than .0001 for all comparisons).

“The greater efficacy of calcipotriol plus 5-FU versus Vaseline plus 5-FU treatment in eliminating actinic keratoses remained highly significant after controlling for the baseline actinic keratosis count, age, and sex of the participants,” they wrote (J Clin Invest. 2016 Nov 21. pii: 89820. doi: 10.1172/JCI89820).

Significantly more of those in the combination group has skin redness during treatment, and 39% experienced a burning sensation on treated skin, compared with 13% of the 5-FU treated group. The rate of scaling and itching of treated skin during treatment was similar, and no patients had crusting or wounding of the treated skin.

“It was incredibly well tolerated. There wasn’t as much discomfort or crusting to where people had to stop. And patients who had used 5-FU in the past preferred this shorter treatment course as well as the type and amount of inflammation they had,” compared with their previous experience, Lynn Cornelius, MD, professor and chief of dermatology, Washington University, Saint Louis, said in an interview. “And it was more efficacious,” added Dr. Cornelius, who was one of the study authors.

Both drugs are readily available, but more studies need to be done to optimize and maximize stability if the drugs are to be stored for any amount of time. Dr. Cornelius and senior author Shadmehr Demehri, MD, of the Center for Cancer Immunology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, have approached pharmaceutical companies regarding commercialization, but have not yet had any agreements.

The trial was investigator initiated. Two authors received grants from the American Skin Association, the Dermatology Foundation, the Burroughs Wellcome Fund, the American Philosophical Society, the La Roche-Posay Research Foundation, and the National Institutes of Health; three investigators were supported by an NIH grant. Dr. Cornelius reported having no financial disclosures.

 

A combined formulation of calcipotriol and 5-fluorouracil (5-FU) outperformed 5-FU alone in reducing the number of actinic keratoses (AKs), with a shorter treatment course and less inflammation than typically seen with 5-FU alone, researchers reported in a study published online in November.

5-FU is effective, but it produces crusting and significant irritation, and is temporarily disfiguring, creating discomfort and inconvenience that often leads to poor patient compliance with treatment.

Robert Boston

In light of recent developments surrounding tumor immunotherapy, the researchers decided to combine 5-FU with calcipotriol (calcipotriene, which is approved for psoriasis), which induces thymic stromal lymphopoietin (TSLP), “an epithelium-derived cytokine and a master regulator of allergic inflammation in the skin,” according to the authors. TSLP in turn recruits anti-tumor T cells.

After demonstrating that the combined treatment reduces AKs in mice, they conducted the study of 131 patients with AKs, randomized to treatment with a cream containing 5% 5-FU and 0.005% calcipotriol, or Vaseline plus 5% 5-FU alone. Participants applied the treatments twice per day for 4 days.

Eight weeks after treatment, the combination group had a mean 87.8% reduction in the number of AKs on the face, compared with 26.3% of the 5-FU controls. The treatment group also had better responses on the scalp (a mean 76.4% reduction in AKs versus 5.7%), right upper extremity (68.8% versus 9.6%), and left upper extremity (79% versus 16.3%). All differences were statistically significant (P less than .0001 for all comparisons).

“The greater efficacy of calcipotriol plus 5-FU versus Vaseline plus 5-FU treatment in eliminating actinic keratoses remained highly significant after controlling for the baseline actinic keratosis count, age, and sex of the participants,” they wrote (J Clin Invest. 2016 Nov 21. pii: 89820. doi: 10.1172/JCI89820).

Significantly more of those in the combination group has skin redness during treatment, and 39% experienced a burning sensation on treated skin, compared with 13% of the 5-FU treated group. The rate of scaling and itching of treated skin during treatment was similar, and no patients had crusting or wounding of the treated skin.

“It was incredibly well tolerated. There wasn’t as much discomfort or crusting to where people had to stop. And patients who had used 5-FU in the past preferred this shorter treatment course as well as the type and amount of inflammation they had,” compared with their previous experience, Lynn Cornelius, MD, professor and chief of dermatology, Washington University, Saint Louis, said in an interview. “And it was more efficacious,” added Dr. Cornelius, who was one of the study authors.

Both drugs are readily available, but more studies need to be done to optimize and maximize stability if the drugs are to be stored for any amount of time. Dr. Cornelius and senior author Shadmehr Demehri, MD, of the Center for Cancer Immunology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, have approached pharmaceutical companies regarding commercialization, but have not yet had any agreements.

The trial was investigator initiated. Two authors received grants from the American Skin Association, the Dermatology Foundation, the Burroughs Wellcome Fund, the American Philosophical Society, the La Roche-Posay Research Foundation, and the National Institutes of Health; three investigators were supported by an NIH grant. Dr. Cornelius reported having no financial disclosures.

 

A combined formulation of calcipotriol and 5-fluorouracil (5-FU) outperformed 5-FU alone in reducing the number of actinic keratoses (AKs), with a shorter treatment course and less inflammation than typically seen with 5-FU alone, researchers reported in a study published online in November.

5-FU is effective, but it produces crusting and significant irritation, and is temporarily disfiguring, creating discomfort and inconvenience that often leads to poor patient compliance with treatment.

Robert Boston

In light of recent developments surrounding tumor immunotherapy, the researchers decided to combine 5-FU with calcipotriol (calcipotriene, which is approved for psoriasis), which induces thymic stromal lymphopoietin (TSLP), “an epithelium-derived cytokine and a master regulator of allergic inflammation in the skin,” according to the authors. TSLP in turn recruits anti-tumor T cells.

After demonstrating that the combined treatment reduces AKs in mice, they conducted the study of 131 patients with AKs, randomized to treatment with a cream containing 5% 5-FU and 0.005% calcipotriol, or Vaseline plus 5% 5-FU alone. Participants applied the treatments twice per day for 4 days.

Eight weeks after treatment, the combination group had a mean 87.8% reduction in the number of AKs on the face, compared with 26.3% of the 5-FU controls. The treatment group also had better responses on the scalp (a mean 76.4% reduction in AKs versus 5.7%), right upper extremity (68.8% versus 9.6%), and left upper extremity (79% versus 16.3%). All differences were statistically significant (P less than .0001 for all comparisons).

“The greater efficacy of calcipotriol plus 5-FU versus Vaseline plus 5-FU treatment in eliminating actinic keratoses remained highly significant after controlling for the baseline actinic keratosis count, age, and sex of the participants,” they wrote (J Clin Invest. 2016 Nov 21. pii: 89820. doi: 10.1172/JCI89820).

Significantly more of those in the combination group has skin redness during treatment, and 39% experienced a burning sensation on treated skin, compared with 13% of the 5-FU treated group. The rate of scaling and itching of treated skin during treatment was similar, and no patients had crusting or wounding of the treated skin.

“It was incredibly well tolerated. There wasn’t as much discomfort or crusting to where people had to stop. And patients who had used 5-FU in the past preferred this shorter treatment course as well as the type and amount of inflammation they had,” compared with their previous experience, Lynn Cornelius, MD, professor and chief of dermatology, Washington University, Saint Louis, said in an interview. “And it was more efficacious,” added Dr. Cornelius, who was one of the study authors.

Both drugs are readily available, but more studies need to be done to optimize and maximize stability if the drugs are to be stored for any amount of time. Dr. Cornelius and senior author Shadmehr Demehri, MD, of the Center for Cancer Immunology and Cutaneous Biology Research Center, Massachusetts General Hospital, Boston, have approached pharmaceutical companies regarding commercialization, but have not yet had any agreements.

The trial was investigator initiated. Two authors received grants from the American Skin Association, the Dermatology Foundation, the Burroughs Wellcome Fund, the American Philosophical Society, the La Roche-Posay Research Foundation, and the National Institutes of Health; three investigators were supported by an NIH grant. Dr. Cornelius reported having no financial disclosures.