The Nambou~ Skin Cancer and Actinic Eye Disease Prevention Trial: Design and Baseline Charackristics of Participants

Addle Green, MB BS, PhD; Diana Battistutta, BSc; Veronim Hart, FACD; David Leslie, FACD; Geoffrey Marks, PhD; Gail Williams, PhD; Philip Gaffney, PhD; Peter Parsons, PhD; Lawrence Hirst, MD, MPH; Christine Frost, MB BS;

INTROIXJCTION

Nonmelanoma skin cancers, namely, basal cell carcinoma U3X’l atv.3 qua- tnws cell carcinoma tSCC1, dre the most commonly occurring cancers in white-skinned populations and reported incidence raks in Australia m-e thtr

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Design of the Nambour Trial 513

highest in the world 111. The principal causal factor is considerecl to be excessive exposure to solar ultraviolet radiation (WI?). Actinic eye disease such as pterygi.~, ocular KC, and cataract are also particularly common in Australia 12-41 A fieid trial that aims to evaluafe the use of sunscreen and B-carotene sup$ements in the prevention of sun-related skin and/or eye disease is presently being undertaken in a Queensland community. This paper describes the general design issues of the study including participant data at baseline and focuses on the skin cancer aspect, while a separate paper will describe the aspects relating tc assessment and prevention of eye disease.

Annual incidents rates of 2.4% for I3C.C and 1.9% for SCC have been estimated among residents of southeastern Queensland aged 20-69 years [S]. Outside Austraha in other fair-skinned populations such as those of the United States and the British IsIes, skin cancer is also of considerable public health importance [6,7] and the incidence appears to have increased steadily over the last few decades [S]. Evidence of the carcinogenic role of UVR is available from observational studies in humans indicating that SCC and, to a lesser extent BCC, occurs most frqdently on sun-exposed parts of tne body and in people who have fair hair and blue eyes and/or tend to bum easily; and that its occurrence is rare in dark-skinned races and in those who migrate as adults from high to low latitudes I5,9,10].

Solar keratoses are far more prevaIent sun-induced skin neoplasias affect- ing, for example, 4OY0 of those under the age of 70 years in the Queensland community of Nambour [I I]. The natural history of solar keratoses is uncer- ta’n, although it is of great clinical importance in assessing treatment and Frevention to know their potentia1 for malignant transformation or spontane- ous remission [7]. Although the number of solar keratoses on tire face is known to be one of the strongest determinants of both SCC and BX [5,1111, there are few relevant data regarding th,e possible bioIogic link 1121, and the detailed events underIying squamous cell transformation and the pathogene- sis of basal cell carcinoma remain uncfear. Apart from actinic skin tumors, perhaps the most common forin of cutaneous solar damage is photoaging, whi?:h is superimposed on innate aging on the face and neck, and results in a leat&ry appearance, deep wrinkles, and furrowing 1131. Photoaging is also strongly assnciated with skin cancer 1141.

At present, investment in skin cxrcer treatment and in prevention cam- paigns in Australia and the United States is immense IlS,lt;]. Among other measures, the use of sunscreens is widely advocated 1171, the above uncer- tainties aboul the mechanisms of W carcinogencsis rntwithstanding. The only evidence available concerning the efficacy of ~ur~.c~eens suggests that the incidence of further benign solar keratoses in persons already affected may be decreased by the regular use of ~unscrcxr for seven months 1181. While the efficacy of sunscrsns in preventing sunburn is well established, there has never been a formal evaluation of the effectivenzz of sunscreens in the prevention of Fkin canctors in humans or of possible harmful effects of regular long-term usz !39]. Ihe National Institntes of i-lealth consensus con- ference statement on 1T’R a::d thcl skin 117’1 tailed attention to the need for an tpidcmiologic study of indiv.duals who nse sunscreens that block ultraviolet 6 KJVBI radiation. Such a study needs to be p~iormed now, when a state of

514 A. Green et 31.

equipoise [2OJ exists regarding sunscreens {those that filter ultraviolet A WVA) as well as UVBl as the long-term protective agent of choice ]17,21].

B-Carotene also has the potential to al:! as a cancer preventive, independent of its role as a precursor of vitamin A. This may be through its antioxidant properties, though this putative mechanism of action has been disputed 1221. Evidence exists for inhibition of carcinogenesis in the lung [23] and large bowel ]24], and large oral doses of B-carotene have been shown to prevent skin cancer in mice after induction by dimethylbenzanthracene (DMBAI or UVB [25,26]. However,. there has been little research in humans to evaluate the potential of B-carotene in the prevention of either BCC or of SCC, which are the two most common types of u;litheliaI tumors. In a cohort of 73,366 women living in the United 5tates and followed for 4 years, nu significant assticiation was seen between risk of KC and dietary carotenoids with vitamin A activity [271. Also a multicenter trial of chemoprevention of non- melanoma skin cancer conducted in 18C5 patients in the United States showed no difference in rates of recurrent BCC between a group taking 50 mg B-carotene daily and a placebo group (281. While second primary skin tumors alone may have been a good model in the latter chemoprevention trial with regard to the lesion being ea+y measured and the short latent period involved, there may have been a large number of recurrent tumors included

in the outcome whose carcinoeenesi: did not reflect the steps involved ab hiti in CUtilWOUS UV carcinogen&s.

The Nambour Skin Cancer and ALM-I~C Eye Disease Prevention Trial being conducted in a community in southeastern Queensland, Austr&a a Gresses a number of these problem:;. It is a field trial of sunscreen anti B-carotene supplements as preventive agents for skin cancer an,3 related artinic skin and eye disease.

OBJECTEYES

Using a factCal design, tiw trial’s main ubjectives are to determine whether daily application of &+-r-protection sonscreen ;iiid i CH dnily inges- tion of 30 mg b-carotene supplen~ents reduces the incidence of bas?l and squamous cell carcinomas, solar keratoscs, and actinic eve disease. and re- tards photoaging in an unselected adult popuiation in Australia over a foho~-up time of 4.5 years. The working hypothesis is that photodamage to PXin is cumulative and progressive: that continuing exposure to UVR pro- motes skin cancer; and tl~us that primary prevention is possible in acluits, des$tc degenerative and premalignant changes that may have already arisen from past exposure.

Nested within the trial are a number of secondaw studies whose aims include the investigation of the immunohistochetrlistry of skin cancers and documentation of thl: natural history of sol,lr kelatases and photoaging, and the study of the epidemiology and prevention of actinic rye disease. The relatic:n of dietary composition to the dcveloprnent of actintr: skin and eye dis~i;e svill bts cxarnined and blood livid profdes of the community partici- pants arc being assessed in relation to the da’ly ingestion of +cnrotme supplements.

Design of the Natnbour Trial 515

STUDY DESIGN

Study Population

The township of Nambour at latitude 26”S and 8.7 m above sea level, lies 100 km north of Brisbane in the Sunshine Coast region of Queensland, and has approximately 8500 residents. In December 1986, a prevaience survey of skin cancer and actinic skin damage was conducted among z random sample of 2095 adult residents of Nambour (drawn from the electoral 1.011: enrollment is compulsory by law) who were then aged between 20 and 69 years Ill]. All persons in the original 1986 study who were able to be contacted in 1992 were invited to take part in the Skin Cancer Prevention Trial. There were 415 participants who did not attend the 1992 clinics, representing 20% of the 1984 study sample, 55% of whom could not be cont?,cted (moved or untraceable, 47?; deceased, 8%). Residents who were invited but did not attend either were not interested or cited health or personal !*easons. All 1675 remaining participants in the 7936 skin cancer prevalence study (plus five Nambour residents who had been sampled in 1986 but not examined) who attended one of five weekend clinics held at the Nambour General Hospital in February and March 1992 were etigible for ic Jusion in the trial. Those who gave written informed consent were randomizell (1626, 97% of those eligibiel. Participants who were taking vitamin suppleme9t.s containing @-carotene and those who reported that they were already applying sunscreen on a strict daily basis were excluded.

Baseline Data Collec tim

A11 participants compkted a standard self-administered questionnaire to obtain demographic information and details of skin cancer .risk factors includ- ing skin type and sun protection habits. Da-ing a personal interview, per- sonal and famify medical histories, srroking habits, and usual patterns of Exercise were recorded, and height, weight, and waist circumference were measured. At the baseline visit, members of the Queensland branch of the Australasian College of DermatoIogists periormed skin examinations of all persons, and the numbers and exact locations of all actinic skin lesions, and any other clioicat signs of solar skin damage were documented. Any lesions diagnosed clinically as WCs or SC&, and a random sample of Icsions diagnosed as solar keratoses, were biopsied for histologic examination by a

single dermatopathol~gist. Silicone imlzssions of the back of Ihe h,znd were obtained from participants less than 50 years, to a~.~ss premature skin aging 1141, and standard photographs of face and hand, vlcre taken. fT3es.e impre+ sirrns and photographs were also taken at the i98C :J*..n-vey, and will be use&, inter alia, h: assess background rates of photo+++) Levels of carotenoder- mia were estimated on the skin of the paim and the cheek using a photomet- ric device Minolta-Airshields Jaundice Meter lOI), whose readings have been vnlic!~teLI against serum p-carotene [29j. In acidition, a r;ir;dcm sample of participants provided a blood sample for detzmiination oi serum p-carotene and lipids, and all participants completed a self--administered, semiquantita- tive food frequency questionnaire to assess usual diet.

516 A. Green et al.

Treatinents

A customized randomization computer program was used to assign all attending the baseline study clinics to one of four treatment groups, namely, both sunscreen and ora p-carotene supplements; sunscreen and oral placebo; p-carotene onty; oral placebo only. Thus each participant takes daily doses of either 30 mg p-carotene tablet:; Itransisomer) or placebo tablets of identical appearance (supplied by Hoffman-La Roche, Nutley, NJ). In addition, half of the trial participants receive a broad-spectrum, sun protection factor (SPFI 15+ sunscreen supplied by Woolworths Limited, Sydney, Australia, under the brand Auscreen Ultrablock Lo-ion SPE’ 15+. Use of a placebo skin cream is considered unethical from two points of view: an oil-in-water emulsion with no active chemicals may enhance UV damage after evaporation of the water component; and people in the trial may use the placebo skin cream rather

than a protective sunscreen in situations that lead to sunburn. The treatment grotocoi involves the self-application of an adequate layer of sunscreen to all expossd sites on the head, neck, and upper limbs every morning, tif;i reappkation advised after heavy sweating or bathing,

Follow-up Schedule

Active intervention in the community will continue for 4.5 years. Thrfx fuli-time research nurses, based on the Sunshine Coast, are responsible for the day-to-day management of participants and liaison with the coordinating center at the Queensland Institute of Medical Research rQlMR> in Brisbane. Each study nurse attends to a randomly allocated one third of the study participants. A contact data base has been defined for each, from which details of any charges in name, address, or health status are incorporated into central files at the QIMR.

Every 3 monlhs, each participant is asked to attend a study clinic at the Nambour General Hospital for distribution of sunscreen {one or more 250 mL bottles. depending on use) and/or sever calendar packs of tablets (bottles and calendar pxks dre individually lebeled rlt the coordinating center prior to collection by the research nurses). For those :mable to attend, treatments are delivered to their homes or mai!ed if they no loi:ger live lu~11ly. At follow-up clinjcs in 1994 and 1996, a11 participants Iincludq those who 1rave with- drawn from the study, as far as ,roAble) will he rrenlininrd by study dermatologists who are masked to treatment ;~‘ll,r~~!ion, wit tr hist&gic cun- firmation of a11 clinically diqnosed L:CCs alld SC& Silicont> impressions of the! back of the hand 1141 will agailk bc obtained to assess progression of rjhotoaging changes.

Monitoring Compliance

Compliance is assessed on a 3-mon:I~ly t-asis when supplies rrF sunscrtl~~n and tablets are replenished. Complinllce with the daily sunscreen regimen is measured by comparin g the wt!ight of sunscreer? used to an empirical stan- dard usage rate hived from average consumption> rrf the sunscreen when used by in group of nonparticipants according to the study pmtocol. Sun-

Design of the Natnbour Trd 517

screen use by people in the control group is monitored by responses to a standard questionnaire delivered annually to participants to obtain inforrna- tion about sun exposure habits including frequency of use of sunscreen in the previous 12 months. Adherence to the tablet regimen is monitored by count- ing remaining tablets at the end of each 3-month period; by monitoring the level of carotenodennia annually using the photometric device [29]; and by determining serum @-carotene in a random sample of participants at 12 and 54 months.

Outcome Measures

While the number of new BCCs and ScCs (first and second primary tumors) will be the main outcome, ail new actinic skin disease is o,C interest. Therefore change in prevalencf of solar keratoses and change i:i degree ti: photoaging of the skin will also be assessed. In order to estimate incidence of skin cancer or solar keratcses brtwecn the bienrijal total skin examinations by dermatologists, study participants carry treatment cards that they present to their loca! doctors whenc-ver a new skin lesion is treated. Their doctors aye asked to iecord on the card dc..::ls of clinical diagnoses and nnatomic sites of any actinic lesions removed, and copies of relevant histqpathology reports are obtained.

STATISTICAL CONSIDERATIONS

Power and Sample Size Estimations

Based on a cohort of 1626, the power of the study is calculated to be 83% to detect a 40% reduction in skin cancer incidence of BCC and SCC combined and 55% to de&t a 30% reduction in skin cancer incidence at the 5% level of significance, associated with the use of sunscreen or p-carotene (i.e., not both simultanzousl) 1. These calculations assume an incidence of skin cancer in the untreated group of 3.1% allowing for aging of the cohort 151, a loss to follow-up at 4.5 years of lo%, a complisncc with sunscreen use and oral p-carotene of 85% (including d,iily use of sunscreen by Sk of controls and of P-carotene supplemenz by 0 % of controls). These estimates of compliance were based on the levels seen in a pilot trial carried out in 1990 m which the feasibility of the planned treatments was tested in an age-stratified random sample of 9h member5 of the eligible study population over an $-month period.

Data Analysis

The number of outcomes (solar L --ztgses, BCC, SCC, actinic eye diseases) experienced in the treatment and contrnl groups fry- L”X!J treatment will be analyzed on an intention-t>treat basis. Il~itially, Poisson regression models will be fitted to determine the inff uence of daily sunscreen and p-carotene use on the incidence of BCC and KC and on the prevalence of solar Lcaratoses. These models will utilize first onset of disease as the outcome since it is sitpposed that the distribution of disease incidence per person wiI1 exhibit

518 A. Green et al.

extra-Poisson variation. Additionally, models that incorpor&e such varia- tions, e.g., those proposed by Breslow [30], will also be used tr> examine this behavior and to model incidence of disease (all occurrences per person) accordingly. An alternative method of analyzing such data will also be employed in the form of random effects 1311 that allow for the iricorporation of an individual’s susceptibihty to disease.

All models will account for the ag+sex stratification of the original cohort as well as the factorial appiication of treatments. Despite randomization and the expectation tha -t confounding effects will be minimal, potential canfound- ing faci ors such as complexion type will be examined and, where appropriate, ir.cluded in all models.

Grading of silicone imprc&ons will allow the rate of photoaging to be defined in terms of an increase in skin damage. Grading will be performed using both thz method described by Beagley and Gibson 1321 with an interob- server reliability of 0.89 I141 and a newly developed method that has been v&dated histologically (L. Fritschi, personal communication). Participants will subsequently be classified according to whether photoaging has taken place, and log-linear models will be used to estimate the relative rates of photoaging (expressed as change in photodamage measured on an ordinal scale), in the treatment groups adjusted for potential cc3nfounders. Addition- a!.l. r. ordinal scale models such as the proportional odds model 1331 will be us& to evaluate photoaging differeirces between treatment groups.

With respect to secondary analyses, variation in nutritional profile will be restricted !:> total energy, P-carotene intake, and dietary fat. As these out- comes are ,normally distributed or can be so transformed, variation among treatment groups will be analyzed with anal, .__ :J ,’ i-of-variance/covariance tuodels. In;errlctian and conFounding effects will be included as above. Re- peated closures ana!!lsis of variance will be used to examine dietary changes over rime h-om the three dietary questionnaire (biennial) administrations.

BASELINE CHARACTERISTICS

Baseline characteristics of recruited participants were :;imilar with respect tu allocated treatment group (rable 1). At trial entry, tlwrc were 917 women (56%) and 709 men overall in the study sample, reflecting the oversampling of women (at IOWPI risk pi skm cancer than men) in the skin cancer prevalence survey, and 455 (25%) participants were under the age of 40 years.

With respect to other risk factors for skin cancer, a little more than half (55%) of the participants assessed themselves as having fair skin while the czt majority (89%) reported that they would usually sunburn on acute sdn expo:,ilre, with (68%) or without (21 “/u) subsequent tanning. There were 430 particip;::ts (26%) who reported a prior diagnt& of skin cancer. Anlung the strongest predictors of risk elf skin cancer besides a pre!*ic\Lls hist<jry of skin cnnccr are solar keratoses, and at baseline ;;ssessment one or ~~~~~~~ keratoses were diagnoscci Ly d &~,;;ztr~!~. .;;i:t i.. ;*I 788 (48% ),. and 15% had more than 10 prevaletli solar keratoses didgnoscd. Approximately 75Y of participants re- ported ever having used su:ls;irern, and of the 1433 participants for whom corrlrrete dietary records were available, 32% used vitanUn supplements in thf preceding 5 ye:lrs.

Design of the Nambour Trial 519

Table 3 3aseline CharacwLtics of Recruited Participants by ‘rreatment Groq3

Nu Sunscreen Sunscreen --

“A” “8” “II” “3” Characteristic Number (%;.) Number (%! Number (%I Number (“/ii)

Total Sex

Gales Fern&s

Age (years) 5 29 30-39 4(1_4sr 50-59

703 skin color

Fair Medium Oiive

Tanning ability Burn only Rum then tan Tan odjr

Solar krratoscs preen t

Sunscreen use Vitamin supplement

US@

Past history uf skin cancer

395 124.3)

185 (46.8) 210 (53.2)

20 : 5.1) 73 I! 8.5)

115 i29.1) S6 (21.8) 75 I19.0) 26 ( 6.6)

203 151.9) 165 (42.2) 23 ( 5.9)

77 ( 19.7) 271 (69.3)

43 01.0)

195 (49.6) 277 (70 7)

115 w.01

113 (23.6)

417 (25.6)

170 (40.8) 247 (59.2)

39 r 9.4) 91 (21.8)

105 (25.21 79 118.9) 78 (18.7) 25 ! 6.0)

239 (57.6) i 49 (35.9) 27 ( 6.5)

92 {22.2, 276 (66.5)

47 (I 1.3)

194 (46.7) 303 (73.0)

119 (32.9)

106 (25.4)

409 (25.1)

175 (42.8) 234 (57.2)

31 ( 7.6) 86 [21.0)

116 (28.4) 71 117.4) 70 (17.1) 35 ( w5)

234 (57.2) 150 (36.7) 25 ( 6.1)

84 (20.5) 282 (65.9)

43 (10.5)

199 (48.8) 309 (75.6)

405 (24.9)

179 (44.2) 226 (55.8)

32 ( 7.0) 82 (20.2)

102 (24.9) 97 (24.0) 71 (27.5) 22 ( 5.4)

221 (54.8) 148 I36.7) 34 ( 8.4)

88 (2’1.81 270 (67.0) 45 (11.21

200 (49.8) 302 (74.9)

94 (26.3)

110 (27.2)

UHased on 1433 participants hx whom completcn dietary rcrords WCTP nvailable.

The IS26 participants were similar Lo :!;.ose rvho had taken part in the r?arlier skin cancer survey but were not in i.he ttial, rcga:,ding skin color and tendency to sunburn or suntan. However, perstins betu-ten 40 and 69 years, and those \qho reported being treated for skin cancer in the intervenibtg period, were more likely to be enrolled in the trial compan:d to those in other age groups and those who had not been treated fur skin cancer in the previous 5 years.

CONCLUSION

This ir the only known community-b;,sed trial of prevention of skin cance: It is also the first tial in which the routine daily use of a high-protection sunscreen is being evaluated, as well a? the effectiveness of &carotene sup- p!ements in the prevention of skin tumor,;, III its third year, compliance with the protocol arid treatment regimens have &een ;li expected levels as observed in the pilot study. However, the possibility of increased u?e of sunscreen by controls in the cr?mrr.unit) as a result not only of involvement in the trial but of widespread and inter.sive media cainpaiqns for S-IF protection will be

520 A. Green ct al.

monitored throughout the study period. Results of the ttial with regard to the prevention of solar keratoses will be available at the end of 1994.

This study is supported by the Public Health Research 2nd Development Committee of the National Health and Medical Rescarch Council of Australia, and in part by the ?revent Blindness Foundation.

APPENDIX: NAMBOUR SKIN CANCER AND ACTINIC EYE DISEASE PREVENTION TRIAL COLLA@ORATORS

Dermatologists

John Auld, FACD Graeme Beardmorc, FACD John Coatl?s, FACD Sandra Cor+$on, FACD Portia Ivvifiiar, $ACD Caroline Mercer, FACD Peter ?Yrrdair, FACD Robert Sinclair, FACD Susan Waite, FACD Perry W’lIson, FACD

Dermatopatho!ogist

David Weedl3n, FACP

Nutrition Group

Bronwyn Ashtoll David Jeacocke, MD Anne Russeli

Data Coordinating Centcl

Rachel Gale Toan Luong Jennifer Read

fiunsul:een sllpplies

Auscreen Ultrablxk Lotion SPF 15t (Woolworths Ltd., Sydney, Australia) Don Ross (3~ss Co.smetics Aust. Pty. Ltd., Melbourne, Australia) Ian Dunn ~Woo!wo~ths Ltd., Sydney, Australia)

P-Carotene and placebo supplies

VN Sin@ (Roche Vitamins and Fine Chemicals, Mutley, NJ, L’S,41

Design of the Nambour Trial 521

External Data Monitoring Committee

Charles I+ Hennekens, MD, Chairman

Waiter Willett, hqD Julie Buring, ScD

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