Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm

Abstract

Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage.

Trial registration: ClinicalTrials.gov NCT00601640.

©2015 American Association for Cancer Research.

Figures

Figure 1

(A) Eighteen participants were accrued to the study in the initial phase when an interim analysis was requested due to higher than expected dermatologic adverse events. This interim analysis resulted in a change in formulation and dosing to the interventions. Subject non-completion in this phase was due to halted participation due to the protocol and formulation changes. (B) One hundred and fifty six participants were accrued after the interim analysis. Of these patients, 136 completed the end-of-study assessment. Reasons for subject non-completion of the study included unacceptable clinical toxicity determined by patient or investigator (n=5), subject decision to withdraw (n=9), unrelated concurrent illness (n=1), death due to unrelated causes (n=1), change in eligibility status (n=2), and other (n=2).

Figure 1

(A) Eighteen participants were accrued to the study in the initial phase when an interim analysis was requested due to higher than expected dermatologic adverse events. This interim analysis resulted in a change in formulation and dosing to the interventions. Subject non-completion in this phase was due to halted participation due to the protocol and formulation changes. (B) One hundred and fifty six participants were accrued after the interim analysis. Of these patients, 136 completed the end-of-study assessment. Reasons for subject non-completion of the study included unacceptable clinical toxicity determined by patient or investigator (n=5), subject decision to withdraw (n=9), unrelated concurrent illness (n=1), death due to unrelated causes (n=1), change in eligibility status (n=2), and other (n=2).

Figure 2

Distribution of participants according to the change in the proportion of nuclei assigned to the baseline (BL) category, comparing the end of study values with the initial values for (A) DFMO, (B) Diclofenac, and (C) DFMO and Diclofenac treatment arms.