Abstract A52: A phase III skin cancer chemoprevention study of DFMO in subjects with a history of non-melanoma skin cancer (NMSC): Follow-up of NMSC events greater than 5 years post-study participation

The most commonly diagnosed malignancy in the United States is non-melanoma skin cancer (NMSC) with > 2 million new cases of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) predicted for 2010. The economic burden and increasing incidence in younger populations, especially women, reinforces the value of skin cancer prevention. Health education and prior attempts at skin cancer chemoprevention have had limited success. A strong link between epithelial carcinogenesis and elevated polyamines, together with a series of phase I and II trials, led to a NCI-sponsored phase III double-blind, placebo-controlled skin cancer chemoprevention trial of α-difluoromethylornithine (DFMO) (500 mg/m2/day) for 4–5 years in 291 subjects with a history of NMSC. Subjects receiving DFMO developed significantly fewer BCC s than placebo subjects with an event rate of 0.28 BCC/person/year versus 0.40 BCC/person/year, (P = 0.03; Total BCCs: DFMO 163, placebo 243). DFMO appeared to have minimal effects on SCC incidence (DFMO 0.15 SCC/person/year, placebo 0.19, p=0.56; Total SCCs: DFMO 95, placebo 115). Subjects tolerated DFMO well, and the only significant observed toxicity was increased audiometric hearing loss. A key issue in the clinical viability of a chemoprevention agent after acute effectiveness and/or tolerance is the latent effectiveness and/or toxicity of the agent. Such effects attributable to DFMO have not been assessed. Earlier chemoprevention research has observed positive and negative latent effects with chemopreventive agents. Use of tamoxifen (5 years) for breast cancer prevention provided continued or greater protection for up to 10 years after drug stoppage. On the contrary, early work with retinoids in oral cancer prevention implied a rebound effect with subjects developing more neoplasms upon discontinuation. Also, the recent linkage between isotretinoin and inflammatory bowel disease is a concerning example of toxicity experienced years after use of a chronically administered agent. The continued interest in DFMO as a chemopreventive agent provided cause to update the clinical data and overall health status of the 291 subjects from the phase III skin cancer prevention study of DFMO to understand the sustainability of the observed DFMO effects. After institutional review board approval, we reviewed medical records of 243 subjects who received care at UW Health. Individual records were manually reviewed, and a pending comparative review of data mining by Natural Language Processing will also be completed. Both reviews focused on the skin cancer events by histology, other neoplasia (invasive and non-invasive), significant other diagnoses, and survival. The rate of skin cancer recurrence from end of study drug to the time of last medical contact (the primary endpoint) was compared between subjects randomized to DFMO or placebo using a two-sample test for primary analysis. As a secondary analysis, the rate of skin cancer recurrence from randomization to the time of last medical contact was also compared. In an exploratory analysis, the primary endpoint was analyzed using Poisson regression models to account for the baseline patient/disease characteristics at the time of randomization such as sex and age of patients and pre-study skin cancer history. Data from the 243 subjects totaling over 2,300 person years is undergoing further validation and preliminary data analysis, and will be available shortly. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A52.