DY A Randomized Controlled Trial to Assess Sunscreen Application and Beta Carotene Supplementation in the Prevention of Solar Keratoses ‘Steven Darlington, BSc; Gail Williams, PhD; Rachel Neale, PhD; Christine Frost, MB,BS, PhD; Adele Green, MB,BS, PhD Background: Solar keratoses (SKs) are among the stron- _gest determinants of skin eancer, but litle is known about the success of measures to control these common skin Objectives To determine whether daily sunscreen ap- plication and/or beta carotene supplementation retards the Fale of occurrence of SKs in adults in the medium term, Design: Randomized controlled trial conducted be- ‘oven February 1992 and August 1996, Setting: General community of the subtropical town- ship of Nambour, Australia (latitude, 26” south). Participants: 4 total of 1621 adults aged 25 to 7+ years. sterventions: Participants were randomized to daily use of sunsereen (application of a high-protection sun- sereen to their head, neck, arms, and hands every morn- ing) or application of sunscreen at their usual disere- tionary rate. They were also randomly assigned to take cither one 30-mg tablet of beta carotene or one placebo tablet each day. Main Outcome Measure: Change in the prevalent numberof SKs in the intervention group relative to change fm the control group. Results: The ratio of SK counts in 1994 relative to 1902 was lower in people randomized to daily sunscreen use (2.20; 95% confidence interval, 1.04-1.39) than in those randomized to discretionary sunscreen use (1.57; 05% confidence interval, 1.35-1.84). This 24% reduction is equivalent to the prevention of an average of 1 addi- Udonal SK per person over that time. A reduction in the rate of change of SK prevalence was also seen in the sun- screen intervention group relative to the discretionary sunscreen group between 1994 and 1990, but it was not significant. No effect on the rate of change of prevalent SK counts was seen among those taking beta carotene supplements relative to those taking placebo tablets Conelustons: Daily application of sunscreen retarded the rate of SK acquisition among adults in a subtropical environment, while a beta carotene supplementation of 30 mg/d had no influence on the oceurrence of SK. “Arch Dermatol, 2003;139:451-455 From the Comprehensive ‘Cancer Research Center Population and Clinical Sclences Division, Queensland Institute of Medical Research (Mr Darlington and Drs Neal, Frost and Green) and the ‘School of Population Health University of Quenslan Australia (Dr Willams). The authors have no relevant {financial interes in this article (aepnnyreD) ARCH DERNATOUVOCT AA ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/11721/ on 04/15/2017 KIN CANCER is a major public health issue in white-skinned populations in the United States, Europe, and Austra lis, and the incidence comtin- ues fo tise Solar keratoses (SKs) are mong the strongest determinants of skin cancer tsk. The risks ofthe main types of shi cancer basal clleazcinoma in squs- ‘mous cell carcinoma (BCC and SCC)— are increased 3- to 12-fold in the presence of Sks-" Indeed, ahigh proportion of SCs ae believed to arise in Sks, although the sctual rate of transformation is stall* De- spite the possibilty that controlling SK de- velopment may effectively reduce skin can- cer, few authors have evaluated control measures. This may be explained partly by the difficulty in wacking SKs over ume, given their mulipliity and theirhigh tara. over rate" Also, the SK distribution in the population is highly skewed, with most people having none and a small percent- age of susceptible individuals carrying the greatest burden. For editorial comment see page 527 In a previous randomized con- trolled tial conducted in temperate Aus- tralia among 431 volunteers older than 40 years who had been diagnosed with Sks, sunscreen use in the short term (7 months) was shown to be effective in reducing the occurrence of new SKs and encouraging he remission of existing SKS.” preven= live elect of sunscreen use over was also suggested by the results of an intervention among a small series of 37 (©2003 American Medical Association, All rights reserved.patients 40 years or older who had a history of skin can- cer." Dietary control measures have also been consid cred. Ina single randomized controlled trial, Black et al” showed that cumulative SK count was significantly de- creased among 38 patients randomized to a low-fat diet ‘compared with patients keeping a normal dit. Beta caro- tene supplementation has been observed to reduce the number of skin tumors (including benign papillomas) Since the effectiveness of sunscreen application in. preventing SKs in the general community is unknown and because of the possible elfectiveness of dietary supple- ments, we addressed these questions in a community. bbased intervention study. In the Nambour Trial, ran- dom sample of residents in a subtropical township were followed up over 44 years at regular intervals. In this framework, we assessed whether the auxiliary measures of regularly applying sunscreen to the skin or taking daily beta carotene supplements could prevent the develop- ment of Sks in the community (es PATIENTS ‘This randomized controlled tral to evaluate the prevention of ‘Sks was conducted in conjunction with a tral to evaluate the clfeciveness of daly sunscreen application and beta carotene supplementation in preventing BCCs and SCCs, Fall details of the conduct and outcome of the skin cancer prevention tral have been reported previously." In 1980, 3000 participants aged between 20 and 69 years were randomly selected from the residents of Nambour, a township in southeast Queensland, Aus- tralia (latitude, 26° south), and invited to take part in askin ‘cancer screening survey. Tae eligible for the intervention stay, the 2005 participants ofthe 1086 study were required to alsa lake part in the baseline survey of 1092 and give writen con- sent (o remain in the randomized trial until 1996. Complete skin examinations were earied out in February 1992, August 1904, andl August 1990 by dermatologists involved in the study survey but unaware of treatment allocation. Only tral partici pants who had all 3 skin examinations were included inthis study Participants were randomly assigned to 1 of 4 treatment groups: (1) daily use ofa broad-spectrum sunscreen witha sun protection factor of 16, plus one 30-mg tablet of beta carotene; (@) daily use ofthe same sunsereen, plus one placebo tablet: {G) one daily 30-mg tablet of beta carotene only; and (4) one daily placebo tablet only. Those not randomized to daily stn screen application were asked to continue applying stinsereen attheir own discretion, The use of placebo sunscreen Was nol ‘considered ethical in ths highly exposed population. Daily use fof sunscreen entailed the application of sunscreen to all ex posed siteson the head (lace, and scalp ifexposed), neck, arms, and back of hands every morning, The stdy sunscreen was 3 Standaed cream rated as water resistant with a sun protection factor of 19." Compliance with the requested sunscreen ap- plication regimen was assessed in 2 wayS. Firs, the measured ‘weights of ll returned sunsercen bottles were recorded every 3 months. Second, participants completed questionnaires in the third and filth years of the til, in which they reported their average [requency of sunsereen se ina normal week and their use of other sun protection strategies, among other things ‘The beta carotene and placebo tablets were identical in ex- termal appearance and taste. Participants were advised to take them (aepnnyreD) ARCH DERNTATOUIVOU TY APR TOT (©2003 American Med with meals The dosage of 30 mgd was determined tbe the ow Cat dose of beta carotene that woul be biologically lfecive"” without causing widespread skin discoloration among part Pants Thenuinber of pis remaining in mediation lear packs tras counted every 3 months to asess compliance, Detaled questionnaires about skin clor and reaction to sunlight, stn exposure pater, skin cancer history. and per sonal habit sch ae smoking were completedat the time ofthe 1002 survey and were updated atthe 1996 survey. During cach ofthe 3 skin examinations (in 1992, 199, and 1990), dermatologiss recorded counts of Ss on 14 spa Tate ody sites, An SK was defined asa dsrete regula scaly (eratoid) lesion with or without pigmentation, Counts were recorded as the numberof defined sks observed on each ste, except where this number exceeded 50 or onsite where more than than 5O% ofthe skin surface area was confluent with Kera- toues. On thes ste, SK counts Were said to be indeterminate. “To cxamine SK development more intensively, sila data collection methods were applied oa randomsubssmpleof 100 atlcipants.Parilpante were surveyed every month, fora {otal of 18 months Starting from 1992. A more detailed regi ten was ved fr counting and mapping Sks present on their heads, necks, arms and hands" STATISTICAL METHODS site-specific SK counts were combined to calculate the num- ter of prevalent Ske on the total body at cach skin examina- tion. tn addition, the SK counts on the sites to which sun- screen was applied according tothe treatment protocol (head neck arms, and hand) were summed to calculate the total SK tnumber on sunsreen aplication siles” We examined 4 dis tinct outcomes based on changes in these 2summary SK counts from baseline (February 1993) othe intermediate survey (Ate {st 1994), and fom the 1994 survey tothe inal August 1996 “These 4 outcomes were modeled agsnst the intervention variables, using a general near model that allowed for re- peated measures. The analysis also included the fellowing po- {ental confounding factors recorded tn 1002: sex ae dict tized as "younger than 50 years or “50 yeas or older) eye Color bluelgray.greenfhazel, boven): ha color (blond, hight brown, red, dark brown/blaci) skin reaction to acute sun ex posure (burn only, burn then ta, tan ony); smoking status Creve, ever, curren); previous history of keratinocytc skin cancer and ptenial occupational sua exposure over ali time (mainly outdoors, both indoors and outdoors, mainly indoor). ‘We used a negative binomial distribution to model SK counts in each instance tis known that such dstbtion ts particularly appropriate for modeling count of events tha tend {ocluster within suscepuble individuals, resulting ina propor- tion of sero counts mauch higher than would be expected un- der the Poison model. The fited negative binomial distribu tion showed good agrestent withthe observed dsibution, both visually and formally (goodnese of fittest P= 8). “The models were all ited using the GENMOD proce- dure inthe SAS saistcl software, version 8.0 (SAS Insitute, City, NC) Estimation and evaluation ofsigniiance ofthe n= terventloneffectiveness was achieved by specification ofa yar >interveniion interaction erm nthe model The use of log link function forthe negative binomial model indicates the changes over Ue, and the intervention ellectveness ts mea- sured as relative rather than absolute, effects, For example, for the 1902-1904 period, foreach othe 2 protocols of sunucreen application (daily and discretionary) we obuained an est tated ratio of SK Counts in 1904 relative to 1992. The magn tude of this ratio in the “dally sunscreen” group, relative va the Association, All rights reserved. ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/11721/ on 04/15/2017"Ss nea nd 7205 it Parca aan Suey tr Panipat anne Snyder Ete 2 Decne ae et aid Rade T "Wi Respeat Daly Secon ]| Ue Aiea Dy Sscen "GAs elo Sinecen | [30 Aged Soecren ede Caine Pace i ea Cetine "nd Poste Glan wFoicme Tata Falonp Slat Falonp lesa Falonup fsrertamned Als Suvest} |sonatBameadaAls Sunes |] |s7detBameecatAr Sunes] [stat Eminedat A Snes 1 amined sl Suny 226 amined Suns 500 raid Al Sees 10 Game at ALSunay Tavis ern TWh amare Biinindeern Tin ern ‘Siecow ‘See Cauna Ste Caa Stecoate 73 aang oa 269 Ramang rai 2 Ramage 2 Ramaing reais ‘CONSORT (Consolidated Standards of Repering Tals) dagram shoving the wat patpants though the study. ‘discretionary sunscreen” group (provided by the interaction term and hereafter called the relative ratio [RR] forthe iter- vention) provides a single measurement of the elfect of stn- screen use on the rate of change in the number of prevalent Sks. Allestimates were adjusted for bth the confounders listed above and the other arm of the intervention, These methods ‘vere also applied to the data arising from the substudy, which included observations at 6-month intervals, Es} 0 1647 eligible residents of Nambour who participated inthe baseline skin cancer survey in 1902, 1621 gavesigned ‘consent to participate also in the trial and were randomly allocated to | of the 4 treatment groups (Figure). Of these 1195 (7496 ofthe original trial participants) remained part ‘of both subsequent skin surveys in 1904 and 1996. As shown previously," allocation to treatment was unre- lated to participants’ baseline characteristics relevant to risk ‘of skin cancer, including age, sex, skin type, sun expo- sure, and history of skin cancer"; and there was no sig- nificant difference in SK counts between the treatment ‘groups at allocation, further 79 individuals were ex cluded because they had indeterminate SK counts re- ccordedat any of thesites, but they did not differ from those included regarding treatment group assignment or tisk fac- tors for skin cancer. These exclusions and loss to fol- low-up did not result in alteration of the distribution of risk factors in the popullation over the course of the tral. ‘Among the 1116 (69% of 1621) individuals in- cluded in the analysis, 598 (54%) had no SKs in 1902, 558 (50%) had no SKs in 1004, and 525 (47%) had none in 1996; the mean number of Sks on the whole body was 3.7 in 1992, 4.3 in 1904, and 49 in 1006; and on the pre- (aepnnyreo) ARCH DERNATOLVOC TY APRS (©2003 American Med scribed sunscreen application sites the corresponding, means were 3.3 in 1992, 4.0 in 1994, and 4.5 in 1996. Thus, on average, each adult in the study gained L new SK over the 4/year intervention period, For the Pebrusty 1992 10 August 1994 period, the estimated increase of SKs on the whole body among those applying sunscreen daily was 20%, while it was 57% in the control group (Rabble 1). Thus, the ratio of the in- crease in the number of prevalent SKs in the daily sun- screen application group, compared with that in the dis- eretionary application group, was 76%. For sunscreen application sites, the comparable ratio was 789%. These estimates, adjusted for the potential confounding fac- tors listed above, were statistically significant at the .03 level. For the August 1904 to Auguist 1996 interval, how- ever, the observed effect of the intervention was dimin- ished, The increase in total body SKs for those receiving, daily sunscreen application was 95% of the increase ob- served inthe control group, and a similar result was found for the sunscreen application sites. Abeta carotene supplementation of 30 mg/d showed no significant effect on SK counts in either period (able 2). In the 1992-1004 period the percentage of the increase in prevalent SK counts was almost identical {in each group. In the 1994-1996 period, individuals who received beta carotene supplements had « higher in- crease than individuals who received placebo tablets (20% vs 7%), but this difference was not significant. Results were similar for SK counts on sunscreen application sites, There wassome modification of the eflect ofthe sun- screen intervention in the first period due to age, tan- ring ability, and past history of skin cancer. The RR for the intervention in individuals younger than 50 years was, Association, All rights reserved. ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/11721/ on 04/15/2017‘Table 1. Adjusted Ratios of Solar Keratoses Counts atthe End of Each of the Sunscreen Inlervention, and Relative Ralios Comparing These od Relative to the Beginning for Each Category ato™ (09% contaance interval) Fiboay counts No sunecre 580 157(135.18) 1.18(098-141) Sunscreen 557 120(106-139) 111 (097-128) Pea ato, sunscrenno suntan 076(062.008) 095 075119) Sunecea te cours No suns 580 154 132-179) 1.17(098-40) Sunscreen 557 121 (105-139) 110(096-127) Peat ao, sunscranno suntan 078(068-006) a9s(o75119) jee orb age, ba carotene tavern, aye colo, ha eee chin eacton to seuss exporure, Meine asupatonl sun exporue, smoking status and provus ory of kn cance. ‘Table 2. Adjusted Ratios of Solar Keratoses Counts at the End of Each of the Bola Carotene Intervention, and Relative Ratlos Comparing These od Relative to the Beginning for Each Category rato" 65% Comidence tesa) ae Fiboay counts Bsa crane 52 138(117-159) 1.07(090-127 Prscabo 574 137(110-158) 120(1.08-140) Pelt ao, beta cactenlplasbo 0.80 (0.80-12) 1.48 (090-141) Sunecea te cours Bea crane 52 138 117-161) 1.07(090-127 Prscabo 574 135 (117-155) 120(1.08-140) Peat ato, beta cactenlplasbo 0.98 (070-121) 118 (090-141) “jee or bx age, suneren trventon ej oor, scala ein econo ace sun expos, Matin acypaional sm exposure, smking tate and prvus istry of sn canes 59% (95% confidence interval [CI], 43%-80%), com- Ca 796) in those older than pared with 92% (95% CI, 72% 50 years. People who tanned alter sin exposure ben- Our study found that the number of prevalent SKs in- cefited more from sunsereen application (RR, 70%; 95% creased over the course ofthe tral in all groups, consi CC, 56%-01%) than those who burned (RR, 111%; 05% tent with the rapid accumulation of SKs in adults of this CL, 7496-105%), and a greater effect was seen among age living ina subtropical environment, Despite this, re- people without a history of skin cancer (RR, 68%; 95% questing a random half of participants to apply sun- C1 529%-80%) than those with a history (RR, 96%; 05% screen daily resulted in a decrease in their average rate Cl, 70%-131%). No consistent differences were seen in of SK acquisition, especially in the first 24 years of the the effect of daly sunscreen among current smokers,ex-_trial. The inerease in SK counts between February 1902 smokers, and individuals who never smoked (data not and August 1994 in the intervention group at large was shown). Por the beta carotene intervention between 1992 approximately 24% lower than that experienced by the ‘and 1994, and for both interventions over thesecond pe- control group, and SK acquisition was almost 44% less od, no notable effect modification was observed. in the more intensively monitored subgroup. This s tan- Thesmallersample of participants who had SK counts tamount to the prevention of an average of 1 additional ‘at6-month intervals showed resulls similar to those of the SK per person over that time. whole study population. In each 6-month interval, sun- ‘Our results in the short-to-medium term are con- sereen had a protective effect, although at vary nitudes; however, estimates were less precise sistent with those of the 2 previous intervention stud- s, which showed that sunscreen application slowed the the smaller sample size. For the first © months of 1902, development of SKs." Naylor et al? found a reduction the ratio of SK increase in the sunscreen treatment group in SK aequisition rates among 37 dermatologic patients ‘compared with that in the control group was 83% (95% of approximately 50% per year, and Thompson etal’ re- C1, $2%-132%), rising to 96% (05% C1, 61%-153%) inthe _ ported an actual decrease in mean SK counts over one latter half of that year, and dropping again to 74% (05% | summer among sunscreen users in 431 people with pre- CC, 35%4-00%) over the first 6 months of 1993, Compar- existing SKs. The greater magnitude ofthe protective elfect ing counts recorded in 1902 and at the end of the 18 inthe previous trials” may partly reflect the fact that Nay- month study resulted inan RR of 56% (05% C1,34%-03%). _lorand colleagues tracked only incident (rather than the (aepnny rep) ARCH DERNATOLIOC TY APRS WWW ARCHDERNIATOL COM (©2003 American Medical Association, AIL rights reserved, ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/11721/ on 04/15/2017predominant, prevalent) lesions." and that the previous Australian study" was conducted over one Australian sum- mer (September-March), when protective measures would be expected to have the greatest effect. We suggest that the major reason for the difference in results, however, ‘was the necessary difference in the choice of treatment modality among controls inthis tial compared with the 2 previous trials that were placebo controlled.”* Ourabil- lty to detect a distinct protective effect of daily sun- screen use may have heen limited because our compari son group, given their subtropical environment, were assigned lo use sunscreen at their discretion rather than ‘an inactive placebo."* The lack of a sunscreen placebo might also explain the unexpected decline in the effect of sunscreen that we ‘observed over the second 2-year period of the interven- tion. (No previous sunscreen intervention study has been conducted for more than 2 years.) The decrease in the observed effectiveness is unlikely to be explained by de- ‘ereasing adherence to the sunscreen intervention proto- ‘col stice the SK acquisition rates in the intervention group, in the first and second trial periods were similar. Incon- trast, the magnitude of the SK acquisition rate inthe con- trol group decreased markedly in the second 2-year pe- riod of the trial, suggesting that people in the control group increased their discretional frequency of sunscreen use ‘over the couse ofthe trial. While we cannot accurately ‘quantify this increase because the precise frequency of ssunsereen use among controls at baseline is not known, anecdotally we were aware of the rise among people not assigned to daily use. This increased frequency of sun- sreen application among the controls is consistent with, the predictions of Leventhal etal that an unblinded con- trol group in randomized controlled trials wll alter sub- jects’ behavior to achieve the outcome expected in the ‘experimental group. Such behavioral compensation is par- ticularly likely in trials of long duration."* Daily application of sunscreen was of significantly _greater benclit among participants expected to have fewer Sks at baseline, namely, those who were younger, those who had no history of skin cancer, and those who had darker skin, This suggests that regular sunscreen appli- ‘cation may be more ellective in preventing incident SKS than in promoting the regression of prevalent lesions. ‘Our results were almost identical for SKs on the sun- screen application sites and SKs on the whole body. This is because SKs on sunscreen application sites consis- tently accounted for more than 94% ofthe total SK counts. In future studies involving assessment of SKs, restrict- ing observations to the predominantly affected sites, namely, face, neck, shoulders, arms, and hands, would sullice Supplementary beta carotene intake of 30 mg/d was not associated with the change in the number of preva- lent SKs over ime and this result concurs with the lack of protection alforded by beta carotene supplementa- tion against BCCs and SCs." Approximately 70% of par= Licipants in both the beta carotene and placebo groups took at least 80% of their tablets. Photometric measure: ments confirmed that those in the bela carotene group maintained significantly higher tissue levels of beta caro- tene than those inthe placebo group.» Thus it seems that (aepnnyreo) ARCH DERATOLVOC TY APR TOT (©2003 American Med beta carotene supplementation of 30 mg/d offers litle pro- tection against the development of sun-induced skin tu- mors in humans. Its clear from our results that a daily application of sunscreen can play a strong role in mini- ‘mizing SK acquisition rates in the general community Prevention of SKs will greatly reduce the costs associated with their treatment, and is also a marker ofthe eflective- ness of sunscreens for the prevention of skin eancer. Regt- lar sunscreen use should thus continue to be advocated san important sun protection strategy, including among, those who would be considered at relatively low risk of actinic skin tumors, such as the young or those with skin that tans easily. Accepted for publication October 23, 2002. This study was supported by the Public Health Re- search and Development Committe ofthe National Health sand Medical Research Council of Australia. Mr Darlington ‘was supported by a grant from the Commonwealth Depart- ment of Health and Aged Care, Canberra, Australia Sunscreen was supplied by Ross Cosmetics Australia, Melbourne, and Woolworths Limited, Sydney, Australia. Beta carotene supplements and placebo were supplied by Rache Vitamins and Fine Chemicals, Nutley, NJ. Corresponding author: Rachel Neale, PhD, Compre hhensive Cancer Research Centre, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queens- land, 4029, Australia (e-mail: racheIN@gimr.edu.au). (Es 1. Spl M, Mare es Tad inh incisine ofon-malanoot kin acer WSC) tested nara 1985-005 ae pinay prevention po (yams srtng haan i? nt J ane 19067814418 Ilr LWanstock WA Nenana sn ane the Uni Stasi ec, Av ead Dnt 12049077478 ef Eer Te VC, andinbion LL ach Trad tn ane i- tian ech 17648. Turon 20087 2862 rena Batista LesD Wadena amour Sty Group. Shin anes subtoia Austalan population: neine and ck of ast tion wih acuption. Ar Epidemiol 106.44: 704-1060, aris R Rens, SeleedS- Maly apstomion cf slr actosesto Squanas cel enna, Lancet 1868 795-707 Frost, Wits, Geen High insdence andesite sare tossin a Queensland eommanty. J nest Dermat 2000115273277 Thompson Sly D, Mak duc of or kate by esa sn cron use Eng Mas. 1955 5201147115. Njlr MF, Boyd Fk, Sry OW, Cameron GS HutbreD. Nene KH, High sun peeton ator unsoeesi th suppression of acc neoplasia, Ach er sta 10051-70175, lnc Hed JA. Goldberg Hea Ect low dt on indent etic eras, Eng J Med 00330 1272125 Mabon Roth MM, ins Ml. Cares atfet development of WB i fed skin cance, Phtota Patti 187650708 amber LA Ware WS, Wel BR, Lv Chl, orauee Te po- ete ut onset tcf dary etree ad itain Eon skin tunrgnsisin Se rice. Mr Cace 190620112 Gren A. Willams 6, Neal ea Daly sunsceen aplication and ba ‘artes supplementation in peer ot BOC and SU ofthe saa Somes carole i. Lancet 190354723-728 {an A, Batista D Hat Vt a. Th Nambour ein cance and cic ye ‘ane preven design ancbasline characters partis, Cr trol ln Tats THES 12522, ats Rah Paak, FnpaviekT Harber, ass Bot-caotene aan al photprotcive aint meropa prxoparpyra JAMA 1974228: oa Lana i Naren OR Lert E, Love AR ends LM, The ber syames occa al. rv led T0020 182-46 Association, All rights reserved. ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/derm/11721/ on 04/15/2017