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Tretinoin: An Established Long-term Safety Profile

Tretinoin: An Established Long-term Safety Profile We are writing to address the conclusions in the letter “Topical Tretinoin, Lung Cancer, and Lung-Related Mortality” by Katz.1 The Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) trial2 was a double-blind study conducted to assess the value of tretinoin, 0.1%, cream in the prevention of nonmelanoma skin cancer. Katz1 concludes that while it is not clear whether tretinoin caused the excess lung-related deaths in VATTC, concern was warranted because a causal link was plausible. Results presented by Weinstock et al2 reveal minor imbalances in morbidity predictors such as age, comorbidities, and smoking status, and the authors conclude that a causal relationship between topical tretinoin therapy and death cannot be inferred. Thus, the supposition by Katz1 is in clear contrast to the conclusions of Weinstock et al.2 Katz1 also suggests that individuals who rapidly metabolize tretinoin are more susceptible to developing non–small cell lung cancer and cites a study by Rigas et al3 of the metabolism of orally administered all-trans retinoic acid (ATRA) in healthy subjects and subjects with lung cancer. However, Rigas et al3 found that if ATRA is critical to normal expression of retinoic acid receptor β, then a rapid catabolic phenotype might account for accelerated oxidative activity that results in decreased nuclear ATRA levels. Rigas et al3 also reference studies indicating that retinoid supplements have proven most effective in the treatment and prevention of smoking-related premalignant or squamous cell cancers of the lung, head, and neck. Finally, Rigas et al3 conclude that diminished levels of ATRA and metabolites might result in an increased susceptibility to carcinogenesis and that high levels of ATRA might prevent cells from escaping normal growth controls and progressing to neoplasia after carcinogenic exposure. Katz1 also implicates tretinoin as a disease-causing agent based on data from studies of beta carotene, a vitamin A precursor.4,5 However, published studies that have linked lung cancer incidence in smokers with beta carotene levels have attributed the effect to high doses of oral beta carotene alone, not its metabolites. There are numerous examples of prooxidant activity by beta carotene. Beta carotene may act as a prooxidant under conditions such as those seen in smokers. The beta carotene radical is a strong oxidizing agent and, depending on the microenvironment, may have a long lifetime, which could explain the procarcinogenic effect of beta carotene in smokers.6 Thus, the association between beta carotene and lung cancer is independent of the formation of vitamin A and/or its metabolites and therefore not relevant to tretinoin. The safety of tretinoin has been clearly established through a battery of clinical and toxicologic studies. Long-term clinical studies in humans (up to 2 years) have been conducted without report of severe adverse events or safety concerns.7 Based on (1) the positive tretinoin safety profile of longer than 35 years in currently marketed prescription products, (2) a wide margin of safety from in-use testing, and (3) topical tretinoin's low level of penetration into the bloodstream, we confidently support the safe use of tretinoin in prescription products. Back to top Article Information Correspondence: Dr Powers, Johnson & Johnson Consumer Products Company, Toxicology, 185 Tabor Rd, Morris Plains, NJ 07950 (wpowers@its.jnj.com). Financial Disclosure: Drs Powers and Heremans are employed by Johnson & Johnson Consumer Products Company, a division of Johnson & Johnson, and own Johnson & Johnson stock and options. Dr Shapiro is president of Skinnovations LLC and a consultant to and retiree of Johnson & Johnson. Funding/Support: This study was supported in part by Johnson & Johnson. Role of the Sponsors: The sponsors had no role in the design or conduct of the study; in the collection, analysis, or interpretation of data; or in the preparation review, or approval of the manuscript. References 1. Katz KA Topical tretinoin, lung cancer, and lung-related mortality. Arch Dermatol 2008;144 (7) 945- 946PubMedGoogle ScholarCrossref 2. Weinstock MABingham SFLew RAVeterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group, Topical tretinoin therapy and all-cause mortality. Arch Dermatol 2009;145 (1) 18- 24PubMedGoogle ScholarCrossref 3. Rigas JRMiller VAZhang ZF Metabolic phenotypes of retinoic acid and the risk of lung cancer. Cancer Res 1996;56 (12) 2692- 2696PubMedGoogle Scholar 4. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330 (15) 1029- 1035PubMedGoogle ScholarCrossref 5. Omenn GSGoodman GEThornquist MD Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334 (18) 1150- 1155PubMedGoogle ScholarCrossref 6. Black HS Mechanisms of pro- and antioxidants. J Nutr 2004;134 (11) 3169S- 3170SPubMedGoogle Scholar 7. Kang SBergfeld WGottlieb AB Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin. Am J Clin Dermatol 2005;6 (4) 245- 253PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Dermatology American Medical Association

Tretinoin: An Established Long-term Safety Profile

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References (7)

Publisher
American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0003-987X
eISSN
1538-3652
DOI
10.1001/archdermatol.2009.206
Publisher site
See Article on Publisher Site

Abstract

We are writing to address the conclusions in the letter “Topical Tretinoin, Lung Cancer, and Lung-Related Mortality” by Katz.1 The Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) trial2 was a double-blind study conducted to assess the value of tretinoin, 0.1%, cream in the prevention of nonmelanoma skin cancer. Katz1 concludes that while it is not clear whether tretinoin caused the excess lung-related deaths in VATTC, concern was warranted because a causal link was plausible. Results presented by Weinstock et al2 reveal minor imbalances in morbidity predictors such as age, comorbidities, and smoking status, and the authors conclude that a causal relationship between topical tretinoin therapy and death cannot be inferred. Thus, the supposition by Katz1 is in clear contrast to the conclusions of Weinstock et al.2 Katz1 also suggests that individuals who rapidly metabolize tretinoin are more susceptible to developing non–small cell lung cancer and cites a study by Rigas et al3 of the metabolism of orally administered all-trans retinoic acid (ATRA) in healthy subjects and subjects with lung cancer. However, Rigas et al3 found that if ATRA is critical to normal expression of retinoic acid receptor β, then a rapid catabolic phenotype might account for accelerated oxidative activity that results in decreased nuclear ATRA levels. Rigas et al3 also reference studies indicating that retinoid supplements have proven most effective in the treatment and prevention of smoking-related premalignant or squamous cell cancers of the lung, head, and neck. Finally, Rigas et al3 conclude that diminished levels of ATRA and metabolites might result in an increased susceptibility to carcinogenesis and that high levels of ATRA might prevent cells from escaping normal growth controls and progressing to neoplasia after carcinogenic exposure. Katz1 also implicates tretinoin as a disease-causing agent based on data from studies of beta carotene, a vitamin A precursor.4,5 However, published studies that have linked lung cancer incidence in smokers with beta carotene levels have attributed the effect to high doses of oral beta carotene alone, not its metabolites. There are numerous examples of prooxidant activity by beta carotene. Beta carotene may act as a prooxidant under conditions such as those seen in smokers. The beta carotene radical is a strong oxidizing agent and, depending on the microenvironment, may have a long lifetime, which could explain the procarcinogenic effect of beta carotene in smokers.6 Thus, the association between beta carotene and lung cancer is independent of the formation of vitamin A and/or its metabolites and therefore not relevant to tretinoin. The safety of tretinoin has been clearly established through a battery of clinical and toxicologic studies. Long-term clinical studies in humans (up to 2 years) have been conducted without report of severe adverse events or safety concerns.7 Based on (1) the positive tretinoin safety profile of longer than 35 years in currently marketed prescription products, (2) a wide margin of safety from in-use testing, and (3) topical tretinoin's low level of penetration into the bloodstream, we confidently support the safe use of tretinoin in prescription products. Back to top Article Information Correspondence: Dr Powers, Johnson & Johnson Consumer Products Company, Toxicology, 185 Tabor Rd, Morris Plains, NJ 07950 (wpowers@its.jnj.com). Financial Disclosure: Drs Powers and Heremans are employed by Johnson & Johnson Consumer Products Company, a division of Johnson & Johnson, and own Johnson & Johnson stock and options. Dr Shapiro is president of Skinnovations LLC and a consultant to and retiree of Johnson & Johnson. Funding/Support: This study was supported in part by Johnson & Johnson. Role of the Sponsors: The sponsors had no role in the design or conduct of the study; in the collection, analysis, or interpretation of data; or in the preparation review, or approval of the manuscript. References 1. Katz KA Topical tretinoin, lung cancer, and lung-related mortality. Arch Dermatol 2008;144 (7) 945- 946PubMedGoogle ScholarCrossref 2. Weinstock MABingham SFLew RAVeterans Affairs Topical Tretinoin Chemoprevention (VATTC) Trial Group, Topical tretinoin therapy and all-cause mortality. Arch Dermatol 2009;145 (1) 18- 24PubMedGoogle ScholarCrossref 3. Rigas JRMiller VAZhang ZF Metabolic phenotypes of retinoic acid and the risk of lung cancer. Cancer Res 1996;56 (12) 2692- 2696PubMedGoogle Scholar 4. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330 (15) 1029- 1035PubMedGoogle ScholarCrossref 5. Omenn GSGoodman GEThornquist MD Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334 (18) 1150- 1155PubMedGoogle ScholarCrossref 6. Black HS Mechanisms of pro- and antioxidants. J Nutr 2004;134 (11) 3169S- 3170SPubMedGoogle Scholar 7. Kang SBergfeld WGottlieb AB Long-term efficacy and safety of tretinoin emollient cream 0.05% in the treatment of photodamaged facial skin. Am J Clin Dermatol 2005;6 (4) 245- 253PubMedGoogle ScholarCrossref

Journal

Archives of DermatologyAmerican Medical Association

Published: Sep 1, 2009

Keywords: tretinoin

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