A clinical trial was halted when it was found that patients who use a cream containing tretonoin – a retinoid used for treating acne and other skin conditions – had a higher chance of dying, compared to patients who used a placebo, according to an article in Archives of Dermatology. However, evidence does not seem to suggest that the therapy caused the extra deaths.
Archives of Dermatology is one of the JAMA (Journal of the American Medical Association) journals.
As background information the authors write “The potential of retinoid compounds to prevent cutaneous malignant lesions [skin cancers] has been of considerable interest, and some are effective for this purpose.”
In 1998, the VATTC (Veterans Affairs Topical Tretinoin Chemoprevention) Trial was started to assess whether high-dose therapy with a cream containing one such retinoid, tretinoin, could prevent cancer. A total of 1,131 veterans (97 percent men, average age 71) were randomly assigned to apply either a cream containing 0.1 percent tretinoin or an unmedicated cream daily to their face and ears. They were then examined by a dermatologist every six months, with a planned study end date of Nov. 15, 2004.
A report that was prepared for one of the study’s many oversight committees in 2004 detected a ‘statistically significant increase’ in risk of death among those using tretinoin – resulting in the trial being halted six months early in May 2004.
Martin A. Weinstock, M.D., Ph.D., of the VA Medical Center and Brown University, Providence, R.I., and team examined the data gathered during the study to see whether there was an association between the medication and risk of death.
As death was not the end point of the study, additional efforts were made to identify those who had died during the study and collect more data about their cause of death, including accessing the VA master death file.
The records and original study data indicated that 108 patients in the tretonoin group and 76 in the control group had died before the end of the intervention period, while another 14 in each group died before the end of the study period (2004).
A significantly higher risk of death in the treatment group was found, even after factoring out such variables as age, co-occurring illnesses, and whether the patient had been a smoker.
However, further investigation did not support tretinoin as a cause of death. e.g., there was no clear link between how much cream was used and death. There was no consistency in the causes of death among participants. On the other hand, in the treatment group, 15 patients died of non-small cell lung cancer, 12 of vascular disorders and 15 of respiratory and other chest disorders – causes linked to smoking, which some previous studies have suggested interacts with compounds in some ways similar to tretinoin, but administered systemically, to produce additional health risks. Participants were asked whether they smoked, but their smoking status was not confirmed, potentially affecting the detected associations.
“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. 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,” the authors wrote.
This study was supported by the Cooperative Studies Program (CSP) of the Office of Research and Development, U.S. Department of Veterans Affairs, and the American Cancer Society. OrthoNeutrogena, a division of Ortho-McNeil Pharmaceutical Inc., provided the tretinoin, 0.1 percent, and the vehicle creams. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
Source – JAMA – Archives of Dermatology
Written by – Christian Nordqvist