Calcium, vitamin D, and risk of adenoma recurrence (United States)

Calcium, vitamin D, and risk of adenoma recurrence (United States)

Marıa Elena Martınez1,2,*, James R. Marshall1,2, Richard Sampliner3,4, Jody Wilkinson1 & David S. Alberts1,2,41Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA; 2College of Public Health, University ofArizona, Tucson, Arizona, USA; 3Southern Arizona VA Health Care System, Tucson, Arizona, USA; 4Department ofMedicine, University of Arizona, Tucson, Arizona, USA

Received 2 July 2001; accepted in revised form 7 November 2001

Key words: adenoma recurrence, calcium, colorectal adenoma, vitamin D.

Abstract

Objective: Few data exist regarding the association between calcium intake and adenoma recurrence, and no dataexist for vitamin D. We investigated the role of dietary and supplemental sources of calcium and vitamin D in theetiology of adenoma recurrence.Methods: Analyses were conducted among 1304 male and female participants in the Wheat Bran Fiber (WBF) trialof adenoma recurrence. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidenceintervals (CIs).Results: In the fully adjusted multivariate model, the OR for participants with dietary calcium intake above 1068versus those with intake below 698 mg/day was 0.56 (95% CI¼ 0.39–0.80; p-trend¼ 0.007). Calcium supplemen-tation at doses above 200 mg/day did not affect risk of recurrence. Although a borderline inverse associationbetween dietary vitamin D and recurrence was observed after adjustment for age and gender, the associationweakened in the fully adjusted model (OR¼ 0.78 for individuals in the upper compared to the lower quartile; 95%CI¼ 0.54–1.13). No association was shown for supplemental sources of vitamin D.Conclusions: Results of this study indicate that a higher intake of calcium decreases the risk of adenoma recurrenceby approximately 45%, whereas vitamin D has no significant effect on recurrence rates.

Introduction

The main precursor lesion for colorectal cancer is theadenomatous polyp [1, 2], which can be readily detectedand removed by endoscopic techniques. Because ade-nomas are usually asymptomatic they are often detectedyears after onset. Prevalence of these pre-neoplasticlesions ranges from 20% to 60% [3–6]. Results ofchemoprevention trials of adenoma recurrence [7–9],including our own [10], indicate that recurrence of theselesions ranges from 40% to 50%.Relatively few studies have been published on the

relation between lifestyle factors and adenoma recur-rence. Among these, prospective observational studies

have assessed dietary intake including calcium [11],folate [12], other micronutrients [13], and coffee and tea[14] in the etiology of adenoma recurrence. Retrospec-tive studies, in which adenoma recurrence is ascertainedby self-report, have also assessed a variety of lifestylerisk factors [15–19].The role of calcium or vitamin D in colorectal

neoplasia has been investigated in several study settings.It is hypothesized [20, 21] that calcium reduces colorec-tal cancer risk by binding secondary bile acids andionized fatty acids to form insoluble soaps in the lumenof the colon; calcium might also directly alter colorectalmucosal proliferative activity [22, 23]. The modest effectof calcium intake on risk of colorectal cancer observedin some epidemiologic studies [24, 25] is consistent withfindings from adenoma recurrence trials [8, 26].Although based on fewer published data, support alsoexists for an inverse association between vitamin D andcolorectal cancer [24].

* Address correspondence to: Marıa Elena Martınez, PhD, Arizona

Cancer Center, University of Arizona, PO Box 245024, 1515 N.

Campbell Ave, Tucson, AZ 85724-4024, USA. Ph.: 520-626-8130; Fax:

520-626-9275; E-mail: [email protected]

Cancer Causes and Control 13: 213–220, 2002. 213� 2002 Kluwer Academic Publishers. Printed in the Netherlands.

Chemoprevention trials of adenoma recurrence inwhich data are collected on a variety of lifestyle factorsat baseline provide an excellent setting to assess theetiology of adenoma recurrence with respect to diet andother lifestyle characteristics. The goal of this study wasto assess whether dietary and/or supplemental sources ofcalcium and vitamin D intake were associated with riskof adenoma recurrence.

Materials and methods

Study population

Analyses were conducted among participants in theWBF trial, whose details [27] and results [10] have beenpreviously published. Since the WBF intervention hadno significant effect on adenoma recurrence [10], weevaluated data from all participants in the trial. Thisphase III trial of high versus low fiber was designed tomeasure the effects of three years of WBF supplemen-tation on adenoma recurrence. Men and women 40–80 years of age who had undergone removal of one ormore colorectal adenoma(s) 3 mm or larger at colono-scopy within three months prior to study entry wererecruited from the Phoenix, Arizona, metropolitan area.We excluded individuals with a personal history ofinflammatory bowel disease or hereditary colon cancersyndromes. A total of 1429 participants were random-ized into the trial and 1304 (91.2%) completed the studyby undergoing one or more colonoscopies after ran-domization. The study was approved by the Universityof Arizona Human Subjects Committee and localhospital committees.

Dietary and supplemental intake

We assessed dietary intake from our 113-item ArizonaFood Frequency Questionnaire (AFFQ) that inquiredabout diet during the prior year. Details regarding thedevelopment of the AFFQ [28] and assessment of itsvalidity and reliability [29] have been previously reported.Nutrient calculations for modifications and updates tothe AFFQ were based on data from the United StatesDepartment of Agriculture’s Continuing Survey of FoodIntake of Individuals, 1996 and the United StatesDepartment of Agriculture’s Nutrient Database forStandard Reference, Version 13. The AFFQ contains avitamin/mineral supplement use section that includesdata collected on the brand of multiple vitamin/mineralsupplements and the dose and frequency of single-vitaminand mineral supplements. The vitamin/mineral supple-ment database contains over 180 nutritional supplement

preparations. Because our analyses called for simulta-neous adjustment of nutrients that are highly correlated,we conducted energy adjustment of the nutrients usingthe regression method of Willett et al. [30].

Risk factor and covariate data

Self-administered questionnaires were used to obtaindata on sociodemographic variables, family history ofcolorectal cancer in first-degree relatives, aspirin use,cigarette smoking, and history of polyps prior tobaseline. In addition, we considered baseline adenomacharacteristics as potential confounding variables sincethese have been shown to be significant predictors ofadenoma recurrence in this study population [31].Data on adenoma characteristics (i.e. number, size,location, and histology) were obtained from themedical record and the pathology report, as previouslyreported [31].

Follow-up

The study protocol specified that two follow-up colo-noscopies be performed after the qualifying colono-scopy. The first colonoscopy was to take place one yearafter randomization (to remove polyps missed at thequalifying colonoscopy) and the second two yearsthereafter. However, national recommendations forcolorectal cancer screening changed during the conductof this trial [32, 33], resulting in a decrease in year onecolonoscopies among participants enrolled in the latterpart of the trial. Therefore, we considered a recurrenceas one or more adenomas or colorectal cancer detectedany time after randomization. The mean (SD) follow-upperiod was 36.8 (16.0) months.

Statistical analysis

We explored the association between calcium andvitamin D intake and adenoma recurrence. For contin-uous variables we treated age as such and used quartilecut-points based on the total study population for dietaryand total calcium and vitamin D intake. For supplemen-tal calcium we used the following categories: none,1–200 mg/day, and >200 mg/day; the correspondingcut-points for supplemental vitamin D were: none, 1–400IU/day, and >400 IU/day. Adenoma recurrence status(positive vs negative) was used as the dependent variable.A priori we considered potential confounding variablesthat are suspected or established risk factors for colo-rectal neoplasia. Because we were interested in assessing

214 M.E. Martınez et al.

Table1.Baselinerisk

factorcharacteristics

accordingto

categories

ofcalcium

andvitamin

Dintakea

Characteristicmedianvalue

Totalcalcium

quartile(m

g/day)

Totalvitamin

Dquartile(IU/day)

629

874

1107

1638

44

131

252

600

No.participants

326

326

326

326

326

326

326

326

Age(years)

64:3�9:3

66:4�8:5

66:5�8:9

66:2�8:4

64:5�9:0

67:9�8:1

64:9�9:1

66:2�8:6

Male,n(%

)247(75.8)

246(75.5)

239(73.3)

142(43.6)

226(69.3)

242(74.2)

216(66.3)

190(58.3)

Aspirin

useb,n(%

)91(27.9)

107(32.8)

96(29.5)

74(22.7)

92(28.2)

102(31.3)

87(26.7)

87(26.7)

Previouspolypsc,n(%

)105(36.6)

120(41.7)

114(38.8)

113(39.8)

120(41.5)

99(35.4)

108(37.5)

125(42.2)

Familyhistory

d,n(%

)57(17.5)

53(16.3)

56(17.2)

54(16.6)

51(15.6)

60(18.4)

53(16.3)

56(17.2)

Currentsm

oking,n(%

)57(17.5)

43(13.2)

39(12.0)

39(12.0)

54(16.6)

37(11.4)

51(15.6)

36(11.0)

No.ofcolonoscopies

2:1�0:9

2:0�0:8

2:0�0:8

2:1�0:9

2:0�0:8

2:1�0:9

2:1�0:8

2:0�0:8

Dietary

intake

Energy,kcal

1809�655

2038�683

1986�689

1866�742

1852�723

2054�673

2066�754

1727�572

Totalfat(g)

70:9�13:7

69:9�12:0

68:4�13:1

66:7�13:5

71:5�13:1

68:9�12:8

68:2�13:6

67:2�13:0

Dietary

fiber

(g)

20:0�5:9

22:2�6:8

22:8�7:5

23:4�7:1

21:4�6:8

22:0�6:7

21:9�6:9

23:2�7:4

Alcohol(g)

10:9�22:4

7:5�13:2

6:5�11:0

3:9�8:2

49:1�20:1

8:5�16:1

6:1�12:2

5:2�7:9

Red

meat(g)

72:5�56:9

65:8�47:7

61:1�46:9

50:6�40:2

72:7�57:0

63:3�45:5

63:2�48:8

50:7�40:4

Supplementalcalcium

(mg)

11:6�35:6

34:6�72:1

92:2�170:7

582:8�516:0

117:0�309:4

95:8�297:5

172:8�363:6

335:7�412:3

Supplementalvitamin

D(IU)

65:4�151:8

115:7�189:3

163:7�256:2

227:5�248:2

00:3�5:5

119:6�167:8

452:4�186:6

Adenomacharacteristics

Number

1:7�0:8

1:7�0:8

1:6�0:8

1:6�0:8

1:6�0:8

1:7�0:8

1:7�0:8

1:5�0:8

Sizee

(mm)

10:1�7:5

9:7�8:1

9:7�6:9

10:0�7:0

10:2�7:1

9:4�6:9

10:1�7:9

9:8�7:5

Proximalf,n(%

)80(24.6)

89(24.5)

93(28.6)

88(27.2)

83(25.5)

84(26.1)

88(27.0)

95(29.3)

Villoushistologyg,n(%

)105(32.2)

94(28.8)

89(27.3)

95(29.1)

102(31.3)

98(30.1)

89(27.3)

94(28.8)

aPlus-minusvalues

are

means�SD.

bRegularuse

ofaspirin

intheprevious10years.

cHistory

ofpreviouspolypspriorto

qualifyingcolonoscopy.Data

missingfor151participants.

dHistory

ofcolorectalcancerin

parentorsibling.

eSizeoflargestadenoma.Data

missingforthreeparticipants.

fPresence

ofanyproximaladenoma.Data

missingforsixparticipants.

gPresence

oftubulovillousorvillousadenomas.Data

missingforoneparticipant.

Calcium, vitamin D, and adenoma recurrence 215

the degree of confounding that occurred with inclusion ofadditional variables (i.e. whether the ORs were appre-ciably altered), we computed three separate multiplelogistic regression models [34]. Model 1 included ageand gender (male vs female). Model 2 included covari-ates in model 1 plus number of study colonoscopies (as acontinuous variable) conducted after baseline, self-reported history of polyps prior to baseline (yes vs no),regular use of aspirin in the previous 10 years (yes vsno), dietary fiber (as a continuous variable), and totalvitamin D (for assessing the independent effect ofcalcium) or total calcium (for assessing the independenteffect of vitamin D). Number of colonoscopies wasincluded as a covariate since this is a strong predictor ofadenoma recurrence in our population: the meannumber of colonoscopies (SD) for individuals who didnot recur was 1.8 (0.7) and 2.3 (0.9) for those whorecurred (p < 0.00001). As we previously reported [31],baseline adenoma characteristics were found to beimportant predictors of recurrence; therefore, based onthese published data, we included adenoma number(three or more vs less than three) and location (anyproximal vs non-proximal) in the final set of logisticregression models. The importance of each independentvariable was summarized by its odds ratio (OR) and95% confidence interval (CI). Trend tests were conduct-ed by modeling the quartile-specific category for eachparticipant.

Results

Median intakes of total calcium ranged from 629 mg/day in the lowest quartile to 1638 mg/day in the highestquartile; the corresponding values for total vitamin Dwere 44 IU/day and 600 IU/day, respectively (Table 1).Compared with participants who reported lower intakesof total calcium, those with higher intakes were older;

Table 2. Intake of calcium and risk of adenoma recurrence

Calcium sourcea Recur+/Recur) Model 1b Model 2c Model 3d

Dietary calcium (mg/day)

<698 175/151 1.00 1.00 1.00

698–873 160/166 0.79 (0.58–1.09) 0.78 (0.56–1.09) 0.76 (0.54–1.07)

875–1068 170/156 0.84 (0.62–1.16) 0.87 (0.62–1.23) 0.89 (0.63–1.26)

>1068 134/192 0.61 (0.44–0.84) 0.59 (0.41–0.84) 0.56 (0.39–0.80)

p-Trend 0.006 0.01 0.007

Supplemental calcium (mg/day)

None 399/391 1.00 1.00 1.00

1–200 127/132 0.93 (0.70–1.24) 1.18 (0.81–1.72) 1.12 (0.76–1.64)

>200 113/142 0.88 (0.66–1.19) 0.94 (0.67–1.33) 0.94 (0.67–1.33)

0.33 0.77 0.75

Total calcium (mg/day)

<778 178/148 1.00 1.00 1.00

778–996 175/151 0.90 (0.66–1.23) 0.92 (0.65–1.29) 0.94 (0.66–1.32)

997–1279 148/178 0.64 (0.47–0.88) 0.66 (0.47–0.94) 0.68 (0.48–0.97)

>1279 138/188 0.65 (0.47–0.90) 0.62 (0.42–0.90) 0.62 (0.42–0.90)

p-Trend 0.002 0.004 0.005

a Dietary and total calcium are energy-adjusted by regression method.b Includes age and gender.c Includes covariates in model 1 plus number of colonoscopies, history of polyps prior to baseline, aspirin use, dietary fiber, and total vitamin

D intake.d Includes covariates in model 2 plus location and number of polyps at baseline.

Fig. 1. Odds ratios (ORs) for adenoma recurrence by quartiles of total

(dietary plus supplemental) calcium intake according to wheat bran

fiber intervention arm. ORs (95% CI) for the high-fiber group (r)

were: 1.00, 0.96 (0.60–1.52), 0.64 (0.39–1.05), and 0.78 (0.47–1.31); the

p for trend was 0.18. The corresponding ORs for the low-fiber group

(n) were: 1.00, 0.88 (0.53–1.49), 0.67 (0.39–1.15), and 0.43 (0.24–0.78);

the p for trend was 0.004. The p for interaction was 0.20.


had a lower proportion of males and current smokers;higher intakes of dietary fiber, supplemental calcium,and vitamin D; and lower intakes of total fat, alcohol,and red meat. No appreciable changes or trends acrossquartile categories were observed for the remainingcharacteristics. Similar patterns were shown for theserisk factor characteristics and total vitamin D intake,with the exception of a slight trend toward a higherproportion of proximal adenomas among participantswith high vs low intakes.We assessed the role of energy-adjusted calcium and

vitamin D intake as risk factors for adenoma recurrence.As noted in the statistical analysis section, we computedthree sets of logistic regression models and thereforepresent three corresponding sets of ORs and 95% CIs.For dietary calcium intake (Table 2), inclusion ofcovariates beyond those in model 1 did not materiallyalter the point estimates. In model 3 the OR (95% CI)for individuals in the upper quartile of dietary calciumwas 0.56 (95% CI¼ 0.39–0.80; p-trend¼ 0.007) com-pared to those in the lower quartile. Conversely, use ofcalcium supplements at a dose of greater than 200 mg/day was not associated with risk of recurrence(OR¼ 0.94; 95% CI¼ 0.67–1.33). Intake of total calci-um (dietary plus supplemental sources) was also in-versely associated with adenoma recurrence, albeit aslight attenuation occurred due to the inclusion ofsupplemental calcium sources.

Because wheat bran fiber has been shown to interferewith calcium absorption [35, 36], we explored whetherthe observed inverse association between calcium intakeand adenoma recurrence was modified by the WBFintervention (Figure 1). The results suggest a strongerassociation for total calcium and recurrence amongparticipants in the low-fiber arm than in the high-fiberarm. Among individuals in the high-fiber intervention(13.5 g/day), the ORs (95% CIs) for the total calciumquartiles were: 1.00, 0.96 (0.60–1.52), 0.64 (0.39–1.05),and 0.78 (0.47–1.31); the p for trend was 0.18. Thecorresponding figures for the low-fiber intervention(2 g/day) were: 1.00, 0.88 (0.53–1.49), 0.67 (0.39–1.15),and 0.43 (0.24–0.78); the p for trend was 0.004.When we assessed the role of vitamin D in the etiology

of adenoma recurrence (Table 3), a borderline significantinverse association for dietary vitamin D was observedafter adjustment for age and gender; the OR (95% CI)for participants in the upper vs the lower quartile was0.73 (95% CI¼ 0.53–1.00). Results of model 1 forsupplemental vitamin D and total vitamin D showweak, non-significant associations. Further adjustmentin models 2 and 3 resulted in a weaker, non-significantassociation for dietary vitamin D and null associationsfor supplemental and total vitamin D.In additional models, when we further adjusted these

for cigarette smoking status, family history of colorectalcancer, and red meat, the overall results were not

Table 3. Intake of vitamin D and risk of adenoma recurrence

Vitamin D sourcea Recur+/Recur) Model 1b Model 2c Model 3d

Dietary vitamin D (IU/day)

<59 169/157 1.00 1.00 1.00

59–113 157/169 0.77 (0.57–1.06) 0.79 (0.57–1.11) 0.79 (0.56–1.11)

114–174 167/159 0.83 (0.61–1.14) 0.90 (0.64–1.27) 0.90 (0.63–1.28)

>174 146/180 0.73 (0.53–1.00) 0.81 (0.56–1.16) 0.78 (0.54–1.13)

p-Trend 0.09 0.10 0.31

Supplemental vitamin D (IU/day)

None 432/420 1.00 1.00 1.00

1–400 185/216 0.86 (0.67–1.09) 0.98 (0.75–1.28) 1.02 (0.78–1.33)

>400 22/29 0.79 (0.44–1.40) 0.98 (0.53–1.82) 1.05 (0.56–1.98)

0.17 0.38 0.86

Total vitamin D (IU/day)

<86 168/158 1.00 1.00 1.00

86–174 173/153 0.94 (0.68–1.28) 1.01 (0.72–1.42) 1.01 (0.72–1.43)

175–455 148/178 0.78 (0.57–1.06) 0.88 (0.62–1.25) 0.88 (0.62–1.25)

>455 150/176 0.80 (0.58–1.09) 0.98 (0.68–1.40) 1.02 (0.71–1.47)

p-Trend 0.09 0.79 0.91

a Dietary and total vitamin D are energy-adjusted by regression method.b Includes age and gender.c Includes covariates in model 1 plus number of colonoscopies, history of polyps prior to baseline, aspirin use, dietary fiber, and total calcium

intake.d Includes covariates in model 2 plus location and number of polyps at baseline.


appreciably altered (data not shown). We also conduct-ed analyses of non-energy-adjusted nutrients, includingenergy intake in the multivariate models; no materialdifferences were noted between these and those of theenergy-adjusted nutrients presented in our main analys-es (data not shown). In secondary analysis, we conduct-ed logistic regression analyses of our final models fortotal calcium and vitamin D stratified by gender. Fortotal calcium, although inverse associations with ade-noma recurrence were observed after stratification, theassociations were slightly stronger among females thanmales. For total calcium and adenoma recurrenceamong males, the ORs (95% CIs) were: 1.00, 1.01(0.68–1.51), 0.83 (0.54–1.26), and 0.67 (0.40–1.10) andthose for females were: 1.00, 0.81 (0.40–1.64), 0.42(0.21–0.87), and 0.52 (0.28–0.98). Corresponding resultsfor total vitamin D suggested no difference whenstratified by gender; among males the ORs (95% CIs)were: 1.00, 1.05 (0.69–1.58), 0.97 (0.62–1.50), and 1.01(0.63–1.63) and those among females were: 1.00, 0.92(0.47–1.80), 0.77 (0.41–1.44), and 1.09 (0.60–1.99).

Discussion

Our prospective observational study is the largest todate to address the role of calcium and vitamin D intakein relation to recurrence of adenomatous polyps. Theresults are consistent with approximately a 40–45%reduction in risk of adenoma recurrence associated withhigh calcium intake; the reduction is largely driven bythe effect of dietary calcium, as there is no evidence of areduction from supplemental sources. Conversely, ourresults show a lack of a significant effect for vitamin Dintake and adenoma recurrence rates.Although data from prospective observational studies

of calcium and colorectal cancer are consistent in findingweak inverse associations [24, 37], findings from the fewpublished studies of colorectal adenoma incidence orprevalence do not support this association. Results of arecent meta-analysis addressing the role of calcium andadenoma prevalence [37] showed a summary relativerisk of 1.13 (95% CI¼ 0.91–1.39). Our point estimatesfor dietary calcium intake are similar to those of Hymanet al. [11] in which the OR for adenoma recurrence forparticipants with intake above 1044 mg per day was0.72 (95% CI¼ 0.43–1.22) compared to those withintake less than 610 mg/day; the corresponding rateratio for number of adenomas showed a slightlystronger effect: OR¼ 0.63 (95% CI¼ 0.39–1.02). As isthe case in our study, the authors also reported that useof calcium supplements was not related to risk ofrecurrence. Our study, with more stable point estimates,

showed that both dietary and total calcium wereinversely associated with risk of adenoma recurrence,even after adjustment for other dietary and lifestylevariables, as well as adenoma characteristics. Further-more, our findings of a weaker effect of calcium amongthe high WBF group of participants suggest that theeffect of calcium might be minimized by binding ofcalcium by fiber, as has been suggested in the literature[35, 36]. It is unclear why supplemental calcium was notassociated with recurrence; it is possible that the dose ofsupplemental calcium is too low, as evident from resultsof trial data [8, 26]. Specifically, in the Calcium PolypPrevention Study [8], a significant, albeit modest,reduction in adenoma recurrence was shown with anintervention of 3000 mg of calcium carbonate (1200 mgelemental calcium) versus placebo (RR¼ 0.81; 95%CI¼ 0.67–0.99).To our knowledge, although there is some evidence of

an inverse association between vitamin D and colorectalcancer [24], no published data exist on its relation toadenoma recurrence. Our findings for dietary vitamin Dare consistent with those of a recently published case–control study of 1993 colon cancer cases and 2410controls [25]; however, they are inconsistent with thosefor supplemental vitamin D, in which an inverse, albeitnon-significant, association was observed. As shown inour study, the point estimates for recurrence andvitamin D intake became attenuated and non-significantin our full logistic regression model. One limitation ofthese analyses is the lack of information in regard to sunexposure, an additional source of vitamin D. Given thatstudy participants resided in the Phoenix, Arizona,metropolitan area, it is possible that a vast majorityhave high exposure to sunlight, resulting in an insuffi-cient range of vitamin D levels to assess its relation toadenoma recurrence. However, the recent publishedstudy of Kampman et al. [25], found no associationbetween sunshine exposure and risk of colon cancer.Major strengths of this study include the prospective

study design and the high rate of participants whounderwent repeat colonoscopy, minimizing detectionbias. An additional strength is the consideration of acomprehensive and biologically plausible list of covari-ates, including the characteristics of the baseline adeno-ma, which have been shown to be important predictorsof recurrence in this [31] and other studies [33, 38, 39].One limitation of the present study is that the studypopulation comprises a group of health-conscientious,Caucasian individuals, and the results may not begeneralizable outside of the sociodemographic charac-teristics of this group.Approximately 30% of the US population undergoes

screening by sigmoidosocopy [40]; among those found to


have adenomatous polyps, approximately half will havea recurrence at follow-up examination. Understandingof etiologic lifestyle factors that might decrease thesehigh recurrence rates is potentially of great importance.Results of the present study indicate that high dietarycalcium intake can decrease these recurrence rates byapproximately 40%. Confirmation of these findings inrecently completed adenoma recurrence trials is needed.

Acknowledgements

We thank Ellen Graver, Vern Hartz, Cheryl Kramer,Jose Guillen-Rodrıguez, Anne Marie Stears, Barbaravan Leeuwen, and Robin Whitacre for their expertassistance. We are indebted to the staff at the Phoenixstudy sites for their valuable contribution. This workwas supported in part by Public Health Service grantsCA-41108 and CA-23074 from the National CancerInstitute. Dr Martınez is supported by a Career Devel-opment Award (KO1 CA79069-10) from the NationalCancer Institute.

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Calcium, vitamin D, and risk of adenoma recurrence (United States)