Topical Tretinoin Therapy May Be Associated With Death

Laurie Barclay, MD

January 20, 2009

January 20, 2009 — An association of topical tretinoin therapy with death was observed in a large randomized controlled trial, but the investigators did not infer a causal association because current evidence suggests that is unlikely, according to a report in the January issue of Archives of Dermatology.

"In an effort to clarify the role, if any, of topical retinoids in the prevention of keratinocyte carcinomas (basal cell and squamous cell carcinomas of the skin), we sought to determine whether high-dose therapy with topical tretinoin, 0.1%, could have a chemopreventive effect," write Martin A. Weinstock, MD, PhD, from VA Medical Center, Rhode Island Hospital and Brown University, Providence, and colleagues from the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group.

"We report the halting of the VATTC Trial intervention 6 months before its scheduled end date because mortality in the tretinoin-treated group was higher than in the vehicle control group, and our evaluation of this potentially causal association between tretinoin therapy and increased mortality," the study authors write. "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."

The goal of this analysis was to assess the relationship of topical tretinoin, a commonly used retinoid cream, with all-cause mortality in the VATTC, a blinded randomized chemoprevention trial with 2- to 6-year follow-up at US Department of Veterans Affairs medical centers.

In the VATTC, 1131 veterans, mean age 71 years, were randomly assigned to receive application of tretinoin, 0.1%, or vehicle control cream twice daily to the face and ears. Patients were excluded if they had a very high estimated short-term risk of death. The primary endpoint of this analysis was death, which was not anticipated as an endpoint in the original study design.

Because of an excessive number of deaths in the group receiving tretinoin, the intervention was terminated 6 months early. Post hoc analysis showed minor imbalances in age, comorbidity, and smoking status between groups, all of which were significant predictors of death. However, the difference in mortality between the treatment groups remained statistically significant after adjustment for these imbalances.

"We observed an association of topical tretinoin therapy with death, but we do not infer a causal association that current evidence suggests is unlikely," the study authors write. "We do not conclude that this trial provides appropriate grounds for hesitating to use topical tretinoin in clinical practice in the absence of additional evidence."

Limitations of this study include post hoc analyses, that information on comorbidities was derived from VA databases that may have been incomplete, and that mortality may have resulted from factors not evaluable.

"The biological implausibility, lack of specificity of causes of death, inconsistency with previous experience, weakness of other supportive evidence in our data, and weak statistical signal cast doubt on a potential causal association of topical tretinoin with death in the VATTC Trial," the study authors write. "However, it is important to note that our population of primarily elderly men is different from those previously reported with large-scale topical tretinoin treatment and that our dosages were higher than in these previous studies."

In an accompanying editorial, Lisa M. Schilling, MD, MSPH, and Robert P. Dellavalle, MD, PhD, MSPH, from the Department of Veterans Affairs Medical Center in Denver, Colorado, "highly commend Weinstock et al for reporting and highlighting these results."

They write, "Clearly, future trials of topical retinoids, especially in elderly patients and in current and former smokers, should monitor known mortality risk factors and the outcome of mortality with validated, sound methods. With increased mortality as a foreseeable outcome, rigorous, predetermined stopping rules and appropriate statistical methods will ensure that trials are not halted prematurely owing to invalid (but essential) interim analyses."

The Cooperative Studies Program of the Office of Research and Development, US Department of Veterans Affairs, and the American Cancer Society supported this study. OrthoNeutrogena, a division of Ortho-McNeil Pharmaceutical, Inc, provided the tretinoin, 0.1%, and the vehicle creams. Some of the authors report various financial arrangements with Galderma Laboratories, Johnson & Johnson, Ligand Pharmaceuticals, Intuitive Surgical Devices, Novartis Pharmaceuticals Corp, Actavis US, Allergan Inc, Roche, and/or 3M Co. The editorial was supported in part by Colorado Health Informatics Collaboration Academic Enrichment Funds from the University of Colorado Denver School of Medicine and NCI K07 Cancer Prevention and Control Career Development Award grant.

Arch Dermatol. 2009;145:18–24, 76.

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