title: 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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona. Joanne.Jeter@osumc.edu.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Jeter
authors.affiliation: Division of Dermatology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
authors.affiliation: Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Myrdal
authors.affiliation: Department of Surgery, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: James A
authors.initials: JA
authors.lastname: Warneke
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Janine G
authors.initials: JG
authors.lastname: Einspahr
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Hubert G
authors.initials: HG
authors.lastname: Bartels
authors.affiliation: Department of Pathology, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Michael
authors.initials: M
authors.lastname: Yozwiak
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: Yira
authors.initials: Y
authors.lastname: Bermudez
authors.affiliation: Department of Biostatistics, University of Arizona College of Public Health, Tucson, Arizona.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Optical Sciences Center, College of Optical Sciences, University of Arizona, Tucson, Arizona.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartels
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
mesh_terms: D000287:Administration, Topical; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D016588:Anticarcinogenic Agents / Q000008:administration & dosage; D004008:Diclofenac / Q000008:administration & dosage*; D000518:Eflornithine / Q000008:administration & dosage*; D005260:Female; D005500:Follow-Up Studies; D005542:Forearm / Q000473:pathology* / Q000528:radiation effects; D006801:Humans; D055623:Keratosis, Actinic / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D013472:Sunlight / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D004008:Diclofenac; D000518:Eflornithine