A recently reported association between topical tretinoin and increased mortality is not causal and most likely is due to chance, according to a report.
The interim finding of an unexpected rise in lung cancer incidence and all-cause mortality prompted the premature halt of the Department of Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) trial, a large 6-year study designed to determine whether the treatment could prevent basal and squamous cell skin cancers in patients who already had at least two such keratinocyte carcinomas. Increased lung cancer incidence and mortality had previously been reported with systemically administered compounds closely related to tretinoin.
Dr. Martin A. Weinstock of the Providence (R.I.) VA Medical Center, and his associates in the VATTC trial conducted a post hoc analysis of the mortality data and confirmed an association with mortality—but no definitive causal links. “We do not conclude that this trial provides appropriate grounds for hesitating to use topical tretinoin in clinical practice,” they wrote in the Archives of Dermatology.
In an editorial comment accompanying the report, Dr. Lisa M. Schilling and Dr. Robert P. Dellavalle said that even though the investigators “chalk their results up as a chance finding,” debate about the safety of topical tretinoin will likely continue. Until further evidence emerges to definitively establish the safety or harmfulness of the treatment, physicians should “at a minimum” discuss the VATTC results with their patients who use tretinoin cream—particularly with elderly men, who composed the bulk of the study population.
“This dialogue should include that the results of the VATTC may have been due to chance, but also that the outcome of death was not initially anticipated,” Dr. Schilling and Dr. Dellavalle noted. In addition, “owing to the ad hoc analysis, various important risk factors, such as smoking status, might not have been completely ascertained.”
In their post hoc study, Dr. Weinstock and his associates at six VA medical centers randomly assigned 566 patients to use tretinoin 0.1% cream on the face and ears once or twice daily, and 565 patients to use only the vehicle cream as a control. The mean patient age was 71 years, and 97% were men.
Six months before the scheduled end of the trial, the intervention was terminated because of a statistically significant excess of deaths at that time (82 deaths) in the treatment group, compared with the control group (53 deaths). More deaths were later identified, for a total of 122 in the intervention group and 90 in the control group.
The VATTC trial data showed no dose-response relationship between exposure to topical tretinoin and death risk, as well as no interaction between the medication and smoking in mediating mortality risk. Moreover, “we found it difficult to construct biologically plausible mechanisms that would explain a direct causal link … and we were unable to conceive of a plausible mechanism by which tretinoin could indirectly lead to a fatal outcome,” they wrote (Arch. Dermatol. 2009;145:18–24).
That implausibility, together with “lack of specificity of causes of death, inconsistency with previous experience, weakness of other supportive evidence in our data, and weak statistical signal” led the researchers to their conclusions.
In their editorial comment, Dr. Schilling and Dr. Dellavalle of the VA Medical Center in Denver noted that, unlike other researchers, Dr. Weinstock and the VATTC investigators publicized their unexpected mortality data (Arch. Dermatol. 2009;145:76).
“We highly commend Weinstock et al. for reporting and highlighting these results,” they said.
Dr. Weinstock has received support from Galderma Laboratories L.P., Johnson & Johnson, and Ligand Pharmaceuticals Inc.
This trial does not provide appropriate grounds for hesitating to use topical tretinoin in clinical practice. DR. WEINSTOCK