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Fwd: Excess Deaths in VA Tretinoin-Retin-A Trial-FDA Silent

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ALLIANCE FOR HUMAN RESEARCH PROTECTION Promoting Openness, Full Disclosure, and Accountabilityhttp://www.ahrp.org  and http://ahrp.blogspot.comFYI"I would urge you to cultivate a keenly skeptical attitude toward thepharmacopeia as a whole..."  Sir William Osler, 1907Indeed, even a seemingly harmless topical ointment may pose unanticipatedlethal risks which are undisclosed on the FDA-approved label. A concerned dermatologist, a former FDA medical officer, brought to ourattention the finding of a 6-year randomized clinical trial conducted by theVeterans Administration involving 1,131 elderly veterans. 566 wererandomized to test tretinoin cream (0.1%), and 565 to placebo. Tretinoin, amember of the retinoid class of medications is commonly used for the topicaltreatment of acne and fine lines and wrinkles. It is marketed as Retin-A andRenova, as well as other branded products.The purpose of trial was to establish the effectiveness of Retin-A as achemoprevention intervention for nonmelanoma skin cancer. The trial failedto demonstrate effectiveness as a cancer prevention treatment. Instead,there were statistically significant, unanticipated extra deaths among thoseapplying tretinoin, compared with those given a placebo: the trial wasterminated 6 months early (in 2004).In 2005, the authors published preliminary results in abstract form in theJournal of Investigative Dermatology, stating that there was NOT astatistically significant difference in overall mortality between tretinoinand placebo groups: "We conclude tretinoin did not cause the mortalitydifference between groups, and in retrospect the termination of theintervention was unnecessary."  Four years elapsed before the study results were finally published inJanuary in Archives of Dermatologyhttp://archderm.ama-assn.org/cgi/content/full/145/1/18According to published report, there were significant differences inmortality between retinoid users and those on placebo:Table 1. Cumulative Deaths among 1131 Study Participants, shows that theretinoid treated group consistently had an excess number of deaths comparedto the placebo group: by April 2004, there were 135 deaths:  82 (14%) deathsin retinoid group compared to 53 (9%) placebo.Before the end of intervention in 2004 the deaths climbed to 184: 108 (19%)deaths in retinoid group compared to 76 (14%) placebo.And by the end of study (follow-up phase) there were 212 deaths: 122 (22%)deaths in retinoid group compared to 90 (16%) placebo.Table 3 Cause of Deaths reveals that greatest disparity in deaths betweenthe retinoid group and placebo involved:lung cancer (15 deaths vs 8), respiratory thoractic disorders (15 vs 7), andvascular disorders (12 vs 3)--when deaths from Arteriosclerosis andAtherosclerosis are added, the vascular risk increases to 22 vs 5.  Thestudy investigators attribute the difference to chance.  However, the accompanying editorial (below) suggests caution: "While debate will continue regarding whether the association betweentopical tretinoin and death found in the VATTCresulted from chance or a realbiological effect, untiladditional data from other studies emerge, practitioners should view theresults of the VATTC with discretion. Public health ideally uses theprecautionary principle-thatpossible harm should be avoided before harmful effects are unquestionablyproven.8 At a minimum, this principle should cause prescribing physicians todiscuss the results of the VATTC with elderly men using topical tretinoin." And a published letter (below) cites earlier controlled retinoid trials withsimilar results:"A causal link between tretinoin and mortality due to lung cancer or otherlung diseases is consistent with previous RCT data. Specifically, theAlpha-Tocopherol, Beta Carotene Cancer Prevention Trial 7 and theBeta-Carotene and Retinol Efficacy Trial8 both linked vitamin A-relatedcompounds to lung cancer. Ironically, both trialswere intended to demonstrate that these compounds could prevent lung cancer.In both studies, however, lung cancer rates in subjects taking vitaminA-related substances were, unexpectedly, significantly higher than insubjects taking placebo, leading to early discontinuation of the vitaminA-related interventions in both trials."The FDA has shown utter indifference:  taking no action whatsoever to alertprescribing physicians to the potential lethal risk. The tretinoin labelingfails to reflect the results of the VA study. The principle investigator, Dr. Martin A. Weinstock, MD, PhD, disclosesreceiving financial support from: received support from GaldermaLaboratories, Johnson & Johnson, and Ligand Pharmaceuticals. Themanufacturer of tretinoin, Ortho-McNeil--Janssen Pharmaceutical is adivision of Johnson & Johnson.Contact: Vera Hassner Sharavveracare212-595-8974Arch Dermatol. 2009;145(1):18-24Topical Tretinoin Therapy and All-Cause MortalityMartin A. Weinstock, MD, PhD; Stephen F. Bingham, PhD; Robert A. Lew, PhD;Russell Hall, MD;David Eilers, MD; Robert Kirsner, MD, PhD; Mark Naylor, MD; James Kalivas,MD; Gary Cole, MD;Kimberly Marcolivio, MEd; Joseph Collins, ScD; John J. DiGiovanna, MD; JuliaE. Vertrees, PharmD;for the Veterans Affairs Topical Tretinoin Chemoprevention (VATTC) TrialGroupObjective: To evaluate the relation of topical tretinoin, a commonly usedretinoid cream, with all-cause mortality in the Veterans Affairs TopicalTretinoin ChemopreventionTrial (VATTC). The planned outcome of this trial was risk of keratinocytecarcinoma, and systemic administration of certain retinoid compounds hasbeen shownto reduce risk of this cancer but has also been associated with increasedmortality risk among smokers. Design: The VATTC Trial was a blinded randomized chemoprevention trial, with2- to 6-year follow-up. Oversight was provided by multiple independent committees.Setting: US Department of Veterans Affairs medical centers.Patients: A total of 1131 veterans were randomized. Their mean age was 71years. Patients with a very high estimated short-term risk of death wereexcluded.Interventions: Application of tretinoin, 0.1%, or vehicle control creamtwice daily to the face and ears.Main Outcome Measures: Death, which was not contemplated as an end point inthe original study design.Results: The interventionwas terminated 6months early because of anexcessive number of deaths in the tretinointreated group. Post hoc analysisof this difference revealed minor imbalances in age, comorbidity, andsmoking status, all of which were important predictors of death. Afteradjusting for these imbalances, the difference in mortality between therandomized groups remained statistically significant.Conclusions: We observed an association of topical tretinoin therapy withdeath, but we do not infer a causal association that current evidencesuggests is unlikely.Trial Registration: clinicaltrials.gov Identifier: NCT00007631~~~~~~~~~~Archives of Dermatology. 2009;145(1):18-24EDITORIALDealing With Unanticipated Mortality in a Large Randomized Clinical Trial ofTopical Tretinoin. . . I would urge you to cultivate a keenly skeptical attitude toward thepharmacopeia as a whole. . . . Sir William Osler, 19071Millions of people have used topical tretinoin to treat acne and photoaging.[2-4]In this issue, Weinstock et al 5 report an unexpected result that led to thepremature halt of their randomized, placebo-controlled Department ofVeterans Affairs TopicalTretinoin Chemoprevention(VATTC)trial designed to determine whether topicaltretinoin, 0.1%, cream prevents basal and squamous cell skin cancer in USveterans. Limited topical tretinoin use (up to twice daily to the face and ears) wasassociated with increased death (end-ofintervention hazard ratio, 1.54;P=.01).While some argue that topical tretinoin might increase pulmonary-relatedmortality,6 Weinstock et al5 ultimately reject this explanation and chalktheir resultsup as a chance finding based on the following: (1) minimal systemicabsorption of topical tretinoin; (2) the lack of a dose-responseassociation; (3) the lack of specificityof causes of death; and (4) the lack of a statistical interaction betweentretinoin use and smoking with mortality. (On this last point, asbestos provides the classic epidemiological exampleof an exposure producing a statistical interaction with smoking: smoking andasbestosexposure together result in greater risk of lung cancer than the sum of therisks from the individual exposures.)7 While debate will continue regardingwhether the association between topical tretinoin and death found in theVATTCresulted from chance or a real biological effect, until additional datafrom other studies emerge, practitioners should view the results of theVATTC with discretion.Public health ideally uses the precautionary principle-thatpossibleharmshould be avoided before harmful effects areunquestionablyproven.8 At a minimum, this principle should cause prescribingphysicians to discuss the results of the VATTC with elderly men usingtopical tretinoin. More circumspect practitioners may wish to discuss theresults of the VATTC with all patients using topical tretinoin. Thisdialogue should include that the results of theVATTC may have beenduetochance, but also that the outcome of death wasnot initially anticipated, andowing to the adhoc analysis, various important risk factors, such as smokingstatus, might not have been completely ascertained. These discussionsprovide an opportunity for all health care providers prescribing tretinointo emphasize tobacco prevention and cessation with their patients.9Clearly, future trials of topical retinoids, especially in elderly patientsand in current and former smokers, should mortality with validated, soundmethods. With increasedmortality as a foreseeable outcome, rigorous, predetermined stopping rulesand appropriate statistical methods will ensure that trials are not haltedprematurely owingto invalid (but essential) interim analyses.10-13 Finally, unlike otherinvestigators who have not emphasized unexpected mortality data,14,15 wehighly commend Weinstock et al 5 for reporting and highlighting theseresults.Correspondence: Dr Dellavalle, Dermatology Service, Department of VeteransAffairs Medical Center, 1055 Clermont St, Box 165, Denver, CO 80220 (robert .dellavalle).Financial Disclosure: None reported.Funding/Support: This study was supported in part by Colorado HealthInformatics Collaboration Academic Enrichment Funds from the University ofColorado DenverSchool of Medicine (Drs Schilling and Dellavalle) and NCI K07 CancerPrevention and Control Career Development Award grant K-07CA92550 (DrDellavalle).Additional Contributions: Martin Weinstock, MD, PhD, answered additionalquestions via e-mail regarding the manuscript.REFERENCES1. Osler W. The reserves of life. St Marys Hosp Gaz. 1907;13:95-98.2. Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhees JJ.Topical tretinoin improves photoaged skin. JAMA. 1988;259(4):527-532.3. Swinyer LJ, Swinyer TA, Britt MR. Topical agents alone in acne: a blindassessment study. JAMA. 1980;243(16):1640-1643.4. Goldfarb MT, Ellis CN, Voorhees JJ. Topical tretinoin: its use in dailypractice to reverse photoageing. Br J Dermatol. 1990;122(suppl 35):87-91.5. Weinstock MA, Bingham SF, Lew RA, et al; Veterans Affairs TopicalTretinoin Chemoprevention (VATTC) Trial Group. Topical tretinoin therapy andall-causemortality. Arch Dermatol. 2009;145(1):18-24.6. Katz KA. Topical tretinoin, lung cancer, and lung-related mortality. ArchDermatol. 2008;144(7):945-946.7. Liddell FDK. The interaction of asbestos and smoking in lung cancer. AnnOccup Hyg. 2001;45(5):341-356.8. Goldstein BD. The precautionary principle also applies to public healthactions. Am J Public Health. 2001;91(9):1358-1361.9. Dellavalle RP, Johnson KR. Time for all dermatology societies to adoptsmoke free policies. J Am Acad Dermatol. 2006;54(1):149-150.10. Goodman SN. Stopping at nothing? some dilemmas of data monitoring inclinical trials. Ann Intern Med. 2007;146(12):882-887.11. DeMets DL, Pocock SJ, Julian DG. The agonizing negative trend inmonitoring of clinical trials. Lancet. 1999;354(9194):1983-1988.12. DeMets DL. Futility approaches to interim monitoring by data monitoringcommittees. Clin Trials. 2006;3(6):522-529.13. Nissen SE. ADAPT: The wrong way to stop a clinical trial. PloS ClinTrials. 2006; 1(7):e35.14. Bombardier C, Laine L, Reicin A, et al; VIGOR Study Group. Comparison ofupper gastrointestinal toxicity of rofecoxib and naproxen in patients withrheumatoidarthritis. N Engl J Med. 2000;343(21):1520-1528.15. Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. NEngl J Med. 2006;354(11):1193. ~~~~~~~~~~~~~  COMMENTS AND OPINIONSTopical Tretinoin, Lung Cancer, and Lung-Related MortalityAmid continuing controversies over drug safety,1,2 results of a trial oftopical tretinoin-a commonly used medication for acne3 and skin wrinkles,hyperpigmentation, and roughness4-raise serious concerns for the publichealth. The Veterans Affairs Topical Tretinoin Chemoprevention (VATTC)trial5,6 was a vehicle-controlled randomized controlled trial (RCT) thatstudied whether topical tretinoin, 0.1%, cream applied to the face and earscould prevent nonmelanoma skin cancer.As reported in an abstract published in 2005,6 the study observed 1131subjects for at least 2 years. After 6 years, and about 6 months prior tothe study's scheduled conclusion, a safety monitoring committee stopped thestudy because of excess mortality among subjects who applied tretinoin (n=82deaths [14%]) compared with those who applied vehicle (n=53 [9%]) (P=.01).Differences in mortality from pulmonary disease (12 vs 4) and non-small celllung cancer (NSCLC) (11 vs 4) were reported.5A causal link between tretinoin and mortality due to lung cancer or otherlung diseases is consistent with previous RCT data. Specifically, theAlpha-Tocopherol, BetaCarotene Cancer Prevention Trial 7 and the Beta-Carotene and RetinolEfficacy Trial 8 both linked vitamin A-related compounds to lung cancer.Ironically, both trialswere intended to demonstrate that these compounds could prevent lung cancer.In both studies, however, lung cancer rates in subjects taking vitaminA-related substances were, unexpectedly, significantly higher than insubjects taking placebo, leading to early discontinuation of the vitaminA-related interventions in both trials.A link between tretinoin and lung-related mortality is biologicallyplausible, with the putative culprit not tretinoin itself but harmfultretinoin metabolites. This line of association begins with the finding thattopically applied tretinoin can be absorbed systemically9 and therefore canreach lung tissue. Once inside cells, tretinoincan induce its own metabolism; continuous dosing with tretinoin may lead notto higher levels of tretinoin but to higher levels of tretinoinmetabolites.10 It is those tretinoinmetabolites that may injure lung tissue, particularly in the presence ofcigarette smoke. This was demonstrated in a study that exposed ferrets tobeta 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 proliferativeresponse and squamous metaplasia that was enhanced by exposure to cigarettesmoke.11 A hypothesis linking lung cancer to adverse effects of tretinoinmetabolites is also supported by the finding that patients with certain types of NSCLC (squamous orlarge-cell carcinomas) metabolize tretinoin more rapidly than patients withanother NSCLC type(adenocarcinoma) or patients without lung cancer.12 This study raises thepossibility that rapid metabolizers of tretinoin may be more likely todevelop lung cancer because, compared with normal metabolizers, they have arelative deficiency of tretinoin and a relative excess of injurioustretinoin metabolites present in their lung tissue.Additionally, the link between tretinoin and lung disease may bemultifactorial; others have proposed that tretinoin- mediated downregulationof defensins in lung tissuecontributed to lung-related mortality in the VATTC trial.13It is not clear whether tretinoin caused the excess lungrelated deaths inthe VATTC trial. But concern is warranted, certainly, both because a causallink is plausibleand because topical tretinoin is indicated for the treatment of relativelyminor conditions. Correspondence: Dr Katz, 1360 Mission St, Ste 401, SanFrancisco, CA 94103 (Kenneth.Katz).Financial Disclosure: None reported.REFERENCES:1. Committee on the Assessment of the US Drug Safety System, Baciu A,Stratton K, Burke SP, eds. The Future of Drug Safety: Promoting andProtecting theHealth of the Public. Washington, DC: National Academies Press; 2006.2. Drazen JM, Morrissey S, Curfman GD. Rosiglitazone-continued uncertaintyabout safety. N Engl J Med. 2007;357(1):63-64.3. US National Library of Medicine. Retin-A (tretinoin) Cream, Retin-A(tretinoin) Gel, Retin-A (tretinoin) Liquid [ORTHO DERMATOLOGICAL]. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=3734. Accessed July 8, 2007.4. Renova [package insert]. Raritan, NJ: Ortho Pharmaceutical Corporation.http://www.aboutrenova.com/RENOVA.05.pdf. Accessed July 8, 2007.5. Weinstock MA, Marcolivio K, Bingham S, et al. Topical tretinoin andallcause mortality. J Invest Dermatol. 2005;124:A52.6. Department of Veterans Affairs. Determine the efficacy of topicaltretinoin cream for the prevention of nonmelanoma skin cancer. http://www.clinicaltrials.gov/ct/show/NCT00007631?order=1. Accessed July 22,2007.7. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. Theeffect of vitamin E and beta carotene on the incidence of lung cancer andothercancers in male smokers. N Engl J Med. 1994;330(15):1029-1035.8. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination ofbeta carotene and vitamin A on lung cancer and cardiovascular disease.N Engl J Med. 1996;334(18):1150-1155.9. van Hoogdalem EJ. Transdermal absorption of topical anti-acne agents inman; review of clinical pharmacokinetic data. J Eur Acad Dermatol Venereol.1998;11(suppl 1):S13-S19.10. Rigas JR, Francis PA, Muindi JR, et al. Constitutive variability in thepharmacokinetics of the natural retinoid, all-trans-retinoic acid, and itsmodulationby ketoconazole. J Natl Cancer Inst. 1993;85(23):1921-1926.11. Wang XD, Liu C, Bronson RT, Smith DE, Krinsky NI, Russell M. Retinoidsignaling and activator protein-1 expression in ferrets given beta-carotenesupplementsand exposed to tobacco smoke. J Natl Cancer Inst. 1999;91(1):60-66.12. Rigas JR, Miller VA, Zhang ZF, et al. Metabolic phenotypes of retinoicacid and the risk of lung cancer. Cancer Res. 1996;56(12):2692-2696.13. Rosenberg EW, Skinner RB Jr. Topical retinoids: another piece for theretinoidcigarette-lung cancer puzzle? J Thorac Oncol. 2006;1(7):732.FAIR USE NOTICE: This may contain copyrighted (C ) material the use of whichhas not always been specifically authorized by the copyright owner. Suchmaterial is made available for educational purposes, to advanceunderstanding of human rights, democracy, scientific, moral, ethical, andsocial justice issues, etc. It is believed that this constitutes a 'fairuse' of any such copyrighted material as provided for in Title 17 U.S.C.section 107 of the US Copyright Law. This material is distributed withoutprofit._____________Infomail1 mailing listto send a message to Infomail1-leave =====In accordance with Title 17 U.S.C. Section 107, this material is distributed without profit to those who have expressed a prior interest in receiving the included information for research and educational purposes.

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