title: A randomized, double-blind, placebo-controlled phase 3 skin cancer prevention study of {alpha}-difluoromethylornithine in subjects with previous history of skin cancer.
abstract: Preclinical studies have shown that the inhibition of ornithine decarboxylase (ODC) by alpha-difluoromethylornithine (DFMO) and resultant decreases in tissue concentrations of polyamines (putrescine and spermidine) prevents neoplastic developments in many tissue types. Clinical studies of oral DFMO at 500 mg/m(2)/day revealed it to be safe and tolerable and resulted in significant inhibition of phorbol ester-induced skin ODC activity. Two hundred and ninety-one participants (mean age, 61 years; 60% male) with a history of prior nonmelanoma skin cancer (NMSC; mean, 4.5 skin cancers) were randomized to oral DFMO (500 mg/m(2)/day) or placebo for 4 to 5 years. There was a trend toward a history of more prior skin cancers in subjects randomized to placebo, but all other characteristics including sunscreen and nonsteroidal anti-inflammatory drug use were evenly distributed. Evaluation of 1,200 person-years of follow-up revealed a new NMSC rate of 0.5 events/person/year. The primary end point, new NMSCs, was not significantly different between subjects taking DFMO and placebo (260 versus 363 cancers, P = 0.069, two-sample t test). Evaluation of basal cell (BCC) and squamous cell cancers separately revealed very little difference in squamous cell cancer between treatment groups but a significant difference in new BCC (DFMO, 163 cancers; placebo, 243 cancers; expressed as event rate of 0.28 BCC/person/year versus 0.40 BCC/person/year, P = 0.03). Compliance with DFMO was >90% and it seemed to be well tolerated with evidence of mild ototoxicity as measured by serial audiometric examination when compared with placebo subjects. The analysis of normal skin biopsies revealed a significant (P < 0.05) decrease in 12-0-tetradecanoylphorbol-13-acetate-induced ODC activity (month 24, 36, and 48) and putrescine concentration (month 24 and 36 only) in DFMO subjects. Subjects with a history of skin cancer taking daily DFMO had an insignificant reduction (P = 0.069) in new NMSC that was predominantly due to a marked reduction in new BCC. Based on these data, the potential of DFMO, alone or in combination, to prevent skin cancers should be explored further.
authors.affiliation: University of Wisconsin Paul P. Carbone Cancer Center, Madison, USA. hhbailey@wisc.edu
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
authors.forename: KyungMann
authors.initials: K
authors.lastname: Kim
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Verma
authors.forename: Karen
authors.initials: K
authors.lastname: Sielaff
authors.forename: Paul O
authors.initials: PO
authors.lastname: Larson
authors.forename: Stephen
authors.initials: S
authors.lastname: Snow
authors.forename: Theresa
authors.initials: T
authors.lastname: Lenaghan
authors.forename: Jaye L
authors.initials: JL
authors.lastname: Viner
authors.forename: Jeff
authors.initials: J
authors.lastname: Douglas
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Dreckschmidt
authors.forename: Mary
authors.initials: M
authors.lastname: Hamielec
authors.forename: Marcy
authors.initials: M
authors.lastname: Pomplun
authors.forename: Harry H
authors.initials: HH
authors.lastname: Sharata
authors.forename: David
authors.initials: D
authors.lastname: Puchalsky
authors.forename: Eric R
authors.initials: ER
authors.lastname: Berg
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Havighurst
authors.forename: Paul P
authors.initials: PP
authors.lastname: Carbone
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001299:Audiometry; D002280:Basal Cell Carcinoma / Q000401:mortality / Q000517:prevention & control*; D002294:Carcinoma, Squamous Cell / Q000401:mortality / Q000517:prevention & control*; D004311:Double-Blind Method; D000518:Eflornithine / Q000627:therapeutic use*; D005260:Female; D006309:Hearing / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D055118:Medication Adherence; D008875:Middle Aged; D065108:Ornithine Decarboxylase Inhibitors; D012878:Skin Neoplasms / Q000401:mortality / Q000517:prevention & control*
chemical_list: D000970:Antineoplastic Agents; D065108:Ornithine Decarboxylase Inhibitors; D000518:Eflornithine