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Hi. I've been using topical tretinoin and adapalene (Differin) for several years. Then I stumbled upon this research paper. Have a look. Even if further research obviously is needed, I think it's right to inform people.


Topical Tretinoin, Lung Cancer, and Lung-Related Mortality

Kenneth A. Katz, MD, MSc, MSCE

Amid continuing controversies over drug safety,1-2 results of a trial of topical tretinoin—a commonly used medication for acne3 and skin wrinkles, hyperpigmentation, and roughness4—raise serious concerns for the public health. The Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) trial5-6 was a vehicle-controlled randomized controlled trial (RCT) that studied whether topical tretinoin, 0.1%, cream applied to the face and ears could prevent nonmelanoma skin cancer. As reported in an abstract published in 2005,6 the study observed 1131 subjects for at least 2 years. After 6 years, and about 6 months prior to the study's scheduled conclusion, a safety monitoring committee stopped the study because of excess mortality among subjects who applied tretinoin (n = 82 deaths [14%]) compared with those who applied vehicle (n = 53 [9%]) (P = .01). Differences in mortality from pulmonary disease (12 vs 4) and non–small cell lung cancer (NSCLC) (11 vs 4) were reported.5

A causal link between tretinoin and mortality due to lung cancer or other lung diseases is consistent with previous RCT data. Specifically, the Alpha-Tocopherol, Beta Carotene Cancer Prevention Trial7 and the Beta-Carotene and Retinol Efficacy Trial8 both linked vitamin A–related compounds to lung cancer. Ironically, both trials were intended to demonstrate that these compounds could prevent lung cancer. In both studies, however, lung cancer rates in subjects taking vitamin A–related substances were, unexpectedly, significantly higher than in subjects taking placebo, leading to early discontinuation of the vitamin A–related interventions in both trials.

A link between tretinoin and lung-related mortality is biologically plausible, with the putative culprit not tretinoin itself but harmful tretinoin metabolites. This line of association begins with the finding that topically applied tretinoin can be absorbed systemically9 and therefore can reach lung tissue. Once inside cells, tretinoin can induce its own metabolism; continuous dosing with tretinoin may lead not to higher levels of tretinoin but to higher levels of tretinoin metabolites.10 It is those tretinoin metabolites that may injure lung tissue, particularly in the presence of cigarette smoke. This was demonstrated in a study that exposed ferrets to beta carotene (a vitamin A precursor) or cigarette smoke or both or neither for 6 months; lungs of all ferrets exposed to beta carotene showed a strong proliferative response and squamous metaplasia that was enhanced by exposure to cigarette smoke.11 A hypothesis linking lung cancer to adverse effects of tretinoin metabolites is also supported by the finding that patients with certain types of NSCLC (squamous or large-cell carcinomas) metabolize tretinoin more rapidly than patients with another NSCLC type (adenocarcinoma) or patients without lung cancer.12 This study raises the possibility that rapid metabolizers of tretinoin may be more likely to develop lung cancer because, compared with normal metabolizers, they have a relative deficiency of tretinoin and a relative excess of injurious tretinoin metabolites present in their lung tissue.

Additionally, the link between tretinoin and lung disease may be multifactorial; others have proposed that tretinoin-mediated downregulation of defensins in lung tissue contributed to lung-related mortality in the VATTC trial.13

It is not clear whether tretinoin caused the excess lung-related deaths in the VATTC trial. But concern is warranted, certainly, both because a causal link is plausible and because topical tretinoin is indicated for the treatment of relatively minor conditions.


Correspondence: Dr Katz, 1360 Mission St, Ste 401, San Francisco, CA 94103 ([email protected]).

Financial Disclosure: None reported.

1. Committee on the Assessment of the US Drug Safety System, Baciu A, ed, Stratton K, ed, Burke SP, ed. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: National Academies Press; 2006.

2. Drazen JM, Morrissey S, Curfman GD. Rosiglitazone–continued uncertainty about safety. N Engl J Med. 2007;357(1):63-64. FREE FULL TEXT

3. US National Library of Medicine. Retin-A (tretinoin) Cream, Retin-A (tretinoin) Gel, Retin-A (tretinoin) Liquid [ORTHO DERMATOLOGICAL]. Accessed July 8, 2007.

4. Renova [package insert]. Raritan, NJ: Ortho Pharmaceutical Corporation. Accessed July 8, 2007.

5. Weinstock MA, Marcolivio K, Bingham S; et al. Topical tretinoin and all-cause mortality. J Invest Dermatol. 2005;124:A52.

6. Department of Veterans Affairs. Determine the efficacy of topical tretinoin cream for the prevention of nonmelanoma skin cancer. Accessed July 22, 2007.

7. 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):1029-1035. FREE FULL TEXT

8. Omenn GS, Goodman GE, Thornquist MD; et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155. FREE FULL TEXT

9. van Hoogdalem EJ. Transdermal absorption of topical anti-acne agents in man; review of clinical pharmacokinetic data. J Eur Acad Dermatol Venereol. 1998;11(suppl 1):S13-S19. ISI | PUBMED

10. Rigas JR, Francis PA, Muindi JR; et al. Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole. J Natl Cancer Inst. 1993;85(23):1921-1926. FREE FULL TEXT

11. Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell M. Retinoid signaling and activator protein-1 expression in ferrets given beta-carotene supplements and exposed to tobacco smoke. J Natl Cancer Inst. 1999;91(1):60-66. FREE FULL TEXT

12. Rigas JR, Miller VA, Zhang ZF; et al. Metabolic phenotypes of retinoic acid and the risk of lung cancer. Cancer Res. 1996;56(12):2692-2696. FREE FULL TEXT

13. Rosenberg EW, Skinner RB Jr. Topical retinoids: another piece for the retinoid-cigarette-lung cancer puzzle? J Thorac Oncol. 2006;1(7):732. PUBMED

Arch Dermatol. 2008;144(7):945-946.

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lol thats kinda interesting...BUT...i dont know if you realize this or not but EVERYTHING causes cancer :-P. Like seriously ,you can find research about almost anything you come in contact with everyday. I doubt retin a once a night is worse than the radio waves were all exposed to every second

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lol thats kinda interesting...BUT...i dont know if you realize this or not but EVERYTHING causes cancer :-P. Like seriously ,you can find research about almost anything you come in contact with everyday. I doubt retin a once a night is worse than the radio waves were all exposed to every second

Good point. Anyway, I think it's the right thing to share the information.

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