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Martin A. Weinstock, MD, PhD; Stephen F. Bingham, PhD; Robert A. Lew, PhD; Russell Hall, MD; David Eilers, MD; Robert Kirsner, MD, PhD; Mark Naylor, MD; James Kalivas, MD; Gary Cole, MD; Kimberly Marcolivio, MEd; Joseph Collins, ScD; John J. DiGiovanna, MD; Julia E. Vertrees, PharmD; for the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group

Arch Dermatol. 2009;145(1):18-24.

Objective  To evaluate the relation of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC). The planned outcome of this trial was risk of keratinocyte carcinoma, and systemic administration of certain retinoid compounds has been shown to reduce risk of this cancer but has also been associated with increased mortality risk among smokers.

Design  The VATTC Trial was a blinded randomized chemoprevention trial, with 2- to 6-year follow-up. Oversight was provided by multiple independent committees.

Setting  US Department of Veterans Affairs medical centers.

Patients  A total of 1131 veterans were randomized. Their mean age was 71 years. Patients with a very high estimated short-term risk of death were excluded.

Interventions  Application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears.

Main Outcome Measures  Death, which was not contemplated as an end point in the original study design.

Results  The intervention was terminated 6 months early because of an excessive number of deaths in the tretinoin-treated group. Post hoc analysis of this difference revealed minor imbalances in age, comorbidity, and smoking status, all of which were important predictors of death. After adjusting for these imbalances, the difference in mortality between the randomized groups remained statistically significant.

Conclusions  We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely.

Trial Registration  clinicaltrials.gov Identifier: NCT00007631

Author Affiliations: Dermatoepidemiology Unit, VA Medical Center (Drs Weinstock and Marcolivio), Department of Dermatology, Rhode Island Hospital and Brown University (Drs Weinstock and DiGiovanna), and Department of Community Health, Brown University (Dr Weinstock, Providence, Rhode Island); Cooperative Studies Program, VA Maryland Health Care System, Perry Point, Maryland (Drs Bingham and Collins); Massachusetts Veterans Epidemiology Research and Information Center, VA Boston Health Care System, Boston, Massachusetts (Dr Lew); VA Medical Center, Division of Dermatology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina (Dr Hall); Department of Dermatology, Edward Hines Jr VA Medical Center, Hines, Illinois (Dr Eilers); VA Medical Center, Department of Dermatology and Cutaneous Surgery, Department of Epidemiology and Public Health, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (Dr Kirsner); VA Medical Center, Oklahoma City, Oklahoma (Dr Naylor); VA Medical Center, Phoenix, Arizona (Dr Kalivas); Department of Dermatology, VA Medical Center, Long Beach, California (Dr Cole); VA Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico (Dr Vertrees).

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