PMC:2918338 / 3625-6327 JSONTXT

{"project":"2_test","denotations":[{"id":"20808599-17409947-58659915","span":{"begin":1165,"end":1166},"obj":"17409947"},{"id":"20808599-18613850-58659916","span":{"begin":1218,"end":1219},"obj":"18613850"}],"text":"COMMENT\nThe VAATC was a 6 year randomized chemoprevention study aimed at reducing the incidence of squamous cell carcinoma and basal cell carcinoma of the skin. Due to unexpected increased mortality in randomized group, trial had to be halted 6 months earlier than the scheduled period.\nDuring the analysis of the possible causes of this mortality, some limitations in the study were noted: Use of multiple review boards instead of a single review board, absence of central oversight committee, lack of data on smoking habits of patients, inclusion of elderly population (who are exposed to many other confounding factors for mortality) and lack of data on some possible factors responsible for deaths.\nThe idea of topical tretinoin application as a cause of mortality appears implausible on theoretical considerations; several questions need to be answered to explain this finding. What could be the cause and mechanism? What could be the dosage of application which can explain this finding?\nOne possible cause of mortality could be respiratory complications especially in smokers, as reported in a previous study in patients on oral isotretinoin and β carotene.[2] Retinoic acid syndrome is another possible cause.[3] Retinoic acid syndrome which may be lethal, is characterized by fever, respiratory distress, serositis, pulmonary oedema and infiltration. It has been reported to occur after administration of all-trans retinoic acid (ATRA) most commonly in patients with acute promyelocytic leukaemia (APL). However percutaneous absorption of tretinoin which varies between 1% and 8% is insufficient to cause lethal respiratory complications that are seen in retinoic acid syndrome. Advanced age of patients (which was not included as an exclusion criterion in the study) and high dose of tretinoin applications could be other factors which may have contributed to increased mortality in the study.\nAn editorial in the same issue urges readers to judge results with discretion till additional data is available. [4] The editorial urges practitioners to discuss these results with elderly patients. The editoial further recommends that prescribing physicians should inform all potential patients about the findings of the study. The editorial also suggested that measures should be taken to design studies with due attention given to risk factors like smoking. Further studies should also have foolproof stopping strategies backed by strong statistical methods to prevent premature termination of trials\nSir Osler's following words of wisdom are relevant even today as the present study also suggests.\n\"I would urge you to cultivate a keenly sceptical attitude toward the pharmacopoeia as a whole\"."}