Blood, Retinol and Zinc Riboflavin Status in Relation to Precancerous Lesions of the Esophagus

(CANCER RESEARCH 48. 2280-2283 April 15, 1988] Blood, Retinol and Zinc Riboflavin Status in Relation to Precancerous Lesions of the Esophagus: Findings from a Vitamin Intervention Trial in the People's Republic of China1

JÃ¼rgenWahrendorf, Nubia MuÃ±oz,Lu Jian-Bang, David I. Thurnham, Massimo Crespi, and Francese Xavier Bosch German Cancer Research Center, InstÃlaleof Epidemiology and Biometry, D-6900 Heidelberg I, Federal Republic of Germany [J. W.]; International Agency for Research on Cancer, 150 Cours Albert Thomas, 69372 Lyon Cedex 08, France [N. M., F. X. B.]; Department of Epidemiology, Henan Cancer Institute, Zhengzhou, Henan Province, People's Republic of China /L. J-BJ; Clinical Investigation Unit, Dudley Road Hospital, Birmingham BIS 7QH and Wolfson Research Laboratories, Queen Elizabeth Medical Centre, Birmingham BIS 2TH, United Kingdom /Â£>./.T.J; and Institute Regina Elena, Viale Regina Elena 291, 00161 Rome, Italy [M. C.J

ABSTRACT was accompanied by atrophy in 12.7% and dysplasia in 2.2% in the placebo group and by atrophy in 12.3% and by dysplasia Data from a double-blind intervention trial in China are reanalyzed to in 2.5% in the vitamin-treated group (10). However, when the explore auxiliary information. The trial had shown that in a high-risk area for esophageal cancer the dietary supplementation of apparently prevalence of micronuclei in the esophageal cells was used as healthy individuals with a combination of retiniti, riboflavin, and zinc did an earlier end point, a statistically significant reduction of this not lead to a different prevalence of precancerous lesions of the esophagus prevalence was observed in the treatment group as compared among those receiving the active treatment compared to a placebo group. to the placebo-treated group (11). However, improvement of blood retinol and zinc levels were also observed In addition to this finding, the auxiliary data collected indi in the placebo group. The logistic regression analysis presented in this cated a need for a more thorough analysis of the results which paper illustrates that those individuals who showed large increases in will be presented in this paper. In particular, the observation retinol, riboflavin, and zinc blood levels were more likely to have a that changes of blood vitamin levels occurred also in persons histologically normal esophagus at the end of the trial. This effect is who received the placebo rather than only in those receiving clearer for retinol than for riboflavin and zinc and it is independent of the vitamin treatment called for a refined analysis. whether the change was caused by the active treatment or occurred otherwise. MATERIALS AND METHODS INTRODUCTION A random sample of 610 subjects in the age group 35-64 years and Precursor lesions of cancer of the esophagus have been de with equal numbers in each sex and age group was drawn from two scribed in endoscopie surveys in areas of Iran and China at high production brigades. A group of 305 subjects received the active treat and low risk for esophageal cancer (1-3). There is some evi ment [15 mg (50,000 IU) retinol, 200 mg riboflavin, and 50 mg zinc] once a week, and a group of 305 individuals received a placebo. The dence suggesting that these lesions are in fact precancerous: a identical-looking treatment or placebo capsules were given weekly to good correlation exists between the prevalence of these lesions the study participants by "barefoot doctors." On entry to the study, at and the incidence of esophageal cancer (1-3), the similar loca the middle of the study, 6 months later, and at the end of the treatment tion in the esophagus of these lesions and of the cancer, the 13.5 months later, the study subjects were interviewed, using a ques results of a small follow-up study showing a high progression tionnaire on smoking, drinking, and dietary habits; they were examined, rate of these lesions to cancer (2), and the similarity between especially for signs of vitamin A and riboflavin deficiencies, and blood these lesions and those induced in nonhuman primates treated samples were drawn for a biochemical analysis of riboflavin, retinol, ÃŸ- with 1-methylnitrosourea (4). Contrary to Europe and America, carotene and zinc. Compliance with the treatment, assessed by inspec tion of follow-up records kept by the barefoot doctors and by changes where alcohol and tobacco explain most of the esophageal in the blood levels 2 and 13.5 months after initiation of the treatment, cancer, the causes of this tumor in China are largely unknown was excellent. The final examination of the 567 (93%) subjects also (5). However, there is some evidence suggesting that deficien included esophagoscopy, with at least two biopsies taken. The histolÃ³g cies of riboflavin, retinol, and zinc might be involved (5-9). To ica! slides were read independently and blindly by three pathologists. study further the role of these micronutrients in the develop After a final diagnosis had been reached by consensus, the code for ment of esophageal cancer, a randomized double-blind inter treatment assignment was opened. vention trial was carried out in Huixian, People's Republic of Data used in this analysis comprise the type of esophageal lesions China, in a population with a high incidence of esophageal found in the histolÃ³gica!material, age, sex, treatment, blood levels of cancer. The aim of the trial was to determine whether a com vitamin A, riboflavin, /3-carotene, zinc, at the beginning and at the end bined treatment with retinol, riboflavin, and zinc could result, of the study, and smoking and drinking habits as assessed at the beginning of the study. after 1 year, in a lower prevalence of precancerous lesions of Logistic regression models as commonly used in the statistical analy the esophagus in the group receiving the active treatment as sis of epidemiolÃ³gica! data (12) were fitted using the presence of compared with the group receiving a placebo. histologically diagnosed esophagitis or more advanced lesions as the No difference in the basic comparison of the prevalence of dependent variable, the others assuming the role of covariables. There precursor lesions of esophageal cancer was observed between were 462 individuals who had complete information on all variables the group receiving the vitamin treatment and the group receiv required. ing a placebo: after 1 year, the prevalence of chronic esophagitis The GLIM package (13) was used to fit logistic regression models with or without atrophy or dysplasia was 45.3% in the placebo for the prevalence odds ratio. group and 48.9% in the vitamin/zinc-treated group. Esophagitis In Table 1, for the three components of the treatment preparation, we give the mean blood levels found at initial and final survey in the Received 6/10/87; revised 12/30/87; accepted 1/18/88. 462 individuals considered in this analysis by treatment group and sex. The costs of publication of this article were defrayed in pan by the payment Comparing these 462 individuals with the 605 contained in Table 2 of of page charges. This article must therefore be hereby marked advertisement in accordance wilh 18 U.S.C. Section 1734 solely to indicate this fact. MuÃ±ozet al., (10), it can be seen that the 462 individuals who had 1Presented at the Fifth Symposium on Epidemiology and Cancer Registries complete information on all variables for this analysis can be viewed as in the Pacific Basin, November 16-21, 1986, Kauai, HI. a representative subsample of the whole study population. The exclu 2280

Table l Blood levels of retinal, riboflavin, and zinc (mean Â±SD) al initial and final survey by treatment group and sex Treatment group PlaceboRetinol

(no. =110)408.0 (no. =119)333.2 (no. =118)411.7Â± (no. =115)333.7

Initial survey (fig/liter) Â±105.7 Â±95.0 104.7 Â±109.6 (fig/liter)RiboflavinFinal survey 486.1Â±109.11.65 41 2.4 Â±103.61.68 56I.3Â±127.71.65 481.4 Â±116.11.67

Initial survey (AC)Â° Â±0.23 Â±0.27 Â±0.26 Â±0.291.29 (AC)ZincFinal survey 1.62Â±0.310.82 1.60 +0.310.76 1.22Â±0.180.83 Â±0.240.78

Initial survey (fig/liter) Â±0.19 Â±0.12 Â±0.17 Â±0.130.95 Â±0.31" Final survey (jig/liter)Males 0.94 Â±0.29Females 0.94 Â±0.27VitaminsMales 0.96 Â±0.29Females AC, activation coefficient.

Table 2 Parameter estimates (odds ratio) offundamental model for logistic alone is considered. Multivariate models including several of these regression of prevalence ofesophageal lesions (esophagitis, atrophy, dysplasia, and cancer) variables simultaneously or interactive effects are commented upon later. In models 1 and 2, the levels at initial and at linai survey are 95% confidence Factor Levels Odds ratio interval considered, in model 3 the absolute difference between final and initial survey, and in model 4 the relative change. In model 5 the relative SexAge change is arbitrarily categorized into more than 20% decrease in retinol, F-44 1.041.0 riboflavin, or zinc status (worse), more than 20% increase (improved), (yr)TreatmentCigarette or neither worsening or improving (unchanged). In each case, we give 45-54 1.27 the parameter estimate with its SE from the logistic regression, a /' for 55+Placebo 1.551.01.271.01.001.00.98,0.88,0.56,0.81,1.811.972.441.831.803.49the statistical significance of including the respective variable as derived from a likelihood ratio test, and an odds ratio estimate which relates VitaminsNo the estimates to the range of levels, namely the 2-fold SD as displayed in Table 1. These odds ratios will be explained in detail in the subse only)Alcoholsmoking (males quent discussions. YesNo Retinol. Models 1 and 2 for retinol show that the prevalence of drinking (males only)M esophageal lesions increases with increasing retinol levels at initial Yes1.0 1.680.59,0.82, survey and decreases with increasing retinol levels at final survey. The first observation reaches marginal statistical significance but has to be interpreted carefully, as the endoscopical and histolÃ³gica! assessment sions were due to technical reasons not related to biochemical status, of esophageal lesions was done 1 year after the initial blood samples treatment group, age, or sex. were taken and after the intermediate supplementation. In Table 1, it Of the 228 males, 167 (73.2%) were current or ex-smokers while this can be seen that the mean of the retinol distribution is about 400 Â¿ig/ was only the case for 2 (0.9%) of the 234 females. However, 85% of liter or above and the SD is about 100 ^g/liter; thus, we illustrate with the male smokers smoked 10 or fewer cigarettes/day. Similarly, 35 the odds ratios given in Table 3 differences of 200 jig/liter. (15.4%) males and 2 (0.9%) females reported regular alcohol drinking A difference of 200 Â¿ig/literof retinol at initial survey is estimated (at least once a week). In view of this difference between males and to correspond to a 1.43-fold [1.43 = exp. (0.0018 x 200)] odds for the females, in subsequent logistic regression analyses only the effect of prevalence ofesophageal lesions, or at final survey to a 0.89-fold odds. smoking and drinking in males were considered. As a consequence, model 3 shows that individuals whose retinol In Table 2, we give the results of fitting a fundamental model levels increase from the initial to the final survey have a lower preva containing sex, age, treatment, smoking, and drinking in males as lence. An increase of 200 fig/liter corresponds to a 0.62-fold reduction independent variables to the prevalence data of all esophageal lesions. of the prevalence odds. There is no difference in the prevalence of esophageal lesions in males The first three models thus show that those individuals who had compared to females. However, the odds ratio of having esophageal lower blood retinol levels at the initial survey, higher blood retinol lesions is increasing with age. The 10-year age categories considered levels at the final survey and, consequently, experienced larger increases demonstrate a significant linear trend in the logarithm of the odds in blood retinol levels, are more likely to have a normal esophagus. ratios (/' = 0.055). When considering age as a continuous variable This picture remains valid when relative increases in retinol levels are comparable results are derived. As indicated by MuÃ±ozetal. (10), there considered (model 4). In this case, the odds ratio corresponds to a 50% is even an increased prevalence of esophageal lesions among those who increase in retinol levels. When this variable of relative change is received the vitamin treatment. In this model, the odds ratio estimate considered in a categorized fashion (model 5), it is seen that those is 1.27 which is in correspondence to the inverse value of 0.852 given individuals whose retinol levels remained unchanged or improved have by MuÃ±ozet al. (10). a lower prevalence of esophageal lesions than those who experienced a Finally, the fundamental model includes two simple yes-no variables worsening of the retinol status, (odds ratios 0.56 and 0.41 vmw.v 1.0). relating to smoking and alcohol drinking among males as reported in Considering the effect of retinol changes separately for each treatment the first survey and already mentioned above. Neither of the variables arm, or for those who had initially low values (below 400 fig/liter), we contributes to the fundamental model in a significant fashion, the could not find any significant interaction of retinol changes with treat relative risk estimate for drinking of alcoholic beverages being 1.68 and ment or initial level on the prevalence ofesophageal lesions, suggesting for smoking 1.00. No further information emerged when the prevalence that the effect of retinol changes on the prevalence of these lesions was of the most advanced esophageal lesions was considered as a dependent not confined to those receiving the active treatment or having had variable or when the smoking and drinking variables were considered initially low levels. in more refined categorizations. Riboflavin. When considering the part of Table 3 relating to ribofla In Table 3, the results are shown of entering into the baseline model vin, it has to be borne in mind that high activation coefficients (>1.30) given in Table 2 different variables relating to blood levels of retino!, represent poor riboflavin status and vice versa. From Table 1, we derived riboflavin, and zinc. In each single entry, the effect of that variable a SD of 0.3 for the distribution of the activation coefficient and have 2281

Table 3 Effect of variables relating W blood levels of retinal, riboflavin, and zinc in logistic regressions analysis (see text) (fig/liter)Model12 Relinol coefficient)Parameter(activation (fig/liter)Parameter

estimate"0.0018 ratio"1.43 ofvariableInitial estimate-0.50 ratio0.74 estimate0.35 ratio1.15 survey Fii,al survey -0.001 0.0008 0.29 0.89 0.22 0.35 0.54 1.14 -0.64 0.36 0.10 0.77 345Type Finalinitialsurvey surveyâ€” -0.0024-0.5020.00.00080.2500.5750.0040.040.04eOdds0.620.781.0 0.481.080.00.290.500.220.100.030.13eOdds1.331.721.00.76-0.62-0.080.00.330.150.550.050.60o.oo0.780.941.0 (Final surveyâ€”initial survey)/initial sur veyWorse

Unchanged -0.574 0.56 -0.28 -2.00 0.14 ImprovedParameter -0.893SE0.00090.566P0.05 0.41Riboflavin-0.50SE0.36 0.39P0.16 0.61Zinc -2.18SE0.61 0.55P0.56 rOdds0.11 " Parameter estimates relate in models 1, 2, and 3 to continuous variables (for range, see Table 1), in model 4 to relative changes, and in model 5 to the three categories. *Odds ratios relate in models 1, 2. and 3 to differences of 2 SDs (see text), in model 4 to a relative change of 50% (0.5), and in model 5 to the three categories. ' P for linear trend along categories.

therefore expressed the odds ratios for models 1, 2, and 3 in reference result of their administration or derived from other sources of to a difference of 0.6 in activation coefficients. For model 4, again a supply. relative change is considered for the odds ratio, whereas in model 5 Although a similar effect is apparent for all three micronu these refer directly to the defined categories. Similar to the picture for trients, the effect for retinol is more consistent in the different retinol, high activation coefficients at initial survey (poor status) and models and the statistical significance is higher than for ribo low activation coefficients at final survey are related to a reduced prevalence of esophageal lesions at the final endoscopical survey. Con flavin and zinc. In addition, considerable improvement in reti sequently, a reduction in riboflavin activation coefficient (increase in nol status was observed among individuals receiving placebo riboflavin status) is associated with a decreased prevalence of esopha while only a modest increase in zinc blood levels and no change geal lesions. The odds ratio for model 3 indicates the estimated 1.33- in riboflavin status were seen among placebo-treated individ fold increase in prevalence odds with an 0.6-increase of the activation uals. coefficient. A 50% increase in activation coefficient (model 4) corre The effect of zinc should be seen in parallel with the effect of sponds to a statistically significant 1.72-fold increase in prevalence retinol due to the metabolic interrelationship of both elements. odds. Zinc is necessary for protein synthesis and acts indirectly on Categorizing the relative changes in a similar fashion to that used retinol metabolism by its effects on tissue growth. Zinc defi for retinol, a decrease in the prevalence of esophageal lesions for those ciency causes growth retardation and decreased retinol levels whose riboflavin status has improved as compared to those whose riboflavin status has worsened is apparent (model 5). However, when (14, 15). Although there is experimental and epidemiological considering the relative riboflavin changes in this categorized fashion, data suggesting that retinol, zinc, and riboflavin might have the effect is no longer statistically significant. As for retinol, interactions some protective effect against the development of certain tu with the treatment and initial level could not be identified. mors, the evidence is not wholly satisfactory (5-9, 15). Zinc. The situation for blood levels of zinc is again very similar to In the present study, the effect of improvement in the blood that of retinol, individuals with lower blood levels at initial survey and levels of retinol, riboflavin, and zinc on the prevalence odds higher levels at final survey experiencing a lower prevalence of esoph ratios of esophageal lesions suggests that there may remain ageal lesions. The odds ratios in Table 3 for models 1, 2, and 3 relate some potential for a beneficial effect from them on the preva to differences of 0.4 ^g/liter, which, according to Table 1, represents lence of precursor lesions of esophageal cancer. The double- approximately 2 SDs. Thus, model 3 indicates that a difference of 0.4 Mg/liter between initial and final survey is associated with a 0.78-fold blind randomized intervention trial was faced with the problem of improvements of retinol status occurring outside the vitamin- reduction of the prevalence odds of chronic esophagitis or more ad vanced lesions. A very strong and statistically significant effect is seen treated group and can thus not conclusively answer this ques when the relative change is categorized into worse, unchanged, and tion. The present analysis, however, suggests that higher doses improved (model 5). of retinol and zinc or administration of the three microelements for a longer period of time may result in the regression of the precancerous lesions of the esophagus. This possibility is sup DISCUSSION ported by the finding of an effect of the intervention when earlier end points were used, namely the prevalence of micro- In the double-blind intervention trial, no effect of the vitamin nucleated esophageal cells, used as an indicator of chromosomal treatment on the prevalence of precancerous conditions could damage (11), and the pattern of cell proliferation of the esoph ageal mucosa.2 be demonstrated. The effect of the treatment on the prevalence of micronuclei in the esophageal cells (11) and increase in blood The improvement in retinol and zinc blood levels which took retinol levels in the placebo-treated group made the investiga place in the placebo group might be real or might be an artifact tion reported here desirable. Judged on the basis of models 3, resulting from systematic differences in measurement between 4, and 5 from Table 3, our data indicate that improvement of the first and final survey, or they might be the result of incorrect blood levels of retinol, but also riboflavin and zinc from the distribution of the capsules. A measurement error is unlikely initial to the final survey is associated with a reduced prevalence since initial and final assays were performed at the same labo of the esophageal lesions. As mentioned above, an interaction ratories using standardized methods and no drift in quality between treatment group or initial level and blood level changes control was observed during the study period.3 A mistake in the did not show any significant effect; thus, the risk of being distribution of the capsules is also unlikely. The weekly capsules diagnosed with esophageal lesions is reduced for such individ were distributed by the barefoot doctors who stripped off the uals who show an improvement in their blood levels of these 1N. MuÃ±ozand M. Lipkin, personal communication. micronutrients irrespective of whether this improvement is the 3D. I. Thurnham, N. MuÃ±oz.J-B. Lu et al., submitted for publication. 2282

self-adhesive label placed on the reverse side of the blister chart tions with low intake of dietary retinol or provitamin A, the containing each individual ration, checked that the subject body may adapt to lower circulating retinol levels. Similar low swallowed the capsules, and placed the label containing the levels of plasma retinol have been observed in Linxian, a county individual's study and week numbers on a follow-up form. nearby our study county (Huixian) in the Henan Province of Periodical review of the follow-up records by field supervisors Northern China, and these levels also rose after supplementa did not reveal any mistake in the distribution. In addition, tion with multi vitamin pills (17). looking at the number of subjects in whom large improvements in retinol and riboflavin levels were observed, it is apparent that REFERENCES although one-half of the subjects in the placebo group showed 1. Crespi, M., MuÃ±oz,N., Grassi, A., Aramesh, B., Amiri, G., and Mojtabai, increases in one or other of the two vitamins, only 12% showed A. Esophageal lesions in northern Iran: a premalignant condition? Lancet, increases in both vitamins.3 This suggests again that a mistake Ã•:217-221, 1979. 2. MuÃ±oz,N., Crespi, M., Grassi, A., Wang, G-Q., Shen, Q., and LÃ¬,Z.C. in the distribution of the capsules is very unlikely. Precursor lesions of esophageal cancer in high-risk populations in Iran and The improvement in retinol and zinc blood levels is then China. Lancet, /: 876-879, 1982. 3. Crespi, M., MuÃ±oz,N., Grassi, A., Shen. Q., Wang, K. J.. and Lin, J. J. probably real and may be due to the difference in time between Precursor lesions of oesophageal cancer in a low-risk population in China: the two surveys. The initial investigation took place during the comparison with high-risk populations. Int. J. Cancer. 34: 599-602, 1984. 4. Adamson, R. H., Krolikowski, J. F., Correa, P., Sieber, S. 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The possible role of riboflavin deficiency in vegetables, is probably caused by most /3-carotene being con epithelial neoplasia. II. Effect on skin tumor development. Cancer (Phila.). 26: 1221-1224. 1970. verted into retinol during intestinal absorption resulting in the 10. MuÃ±oz,N., Wahrendorf, J., Lu, J. B., Crespi, M., Thurnham, D. I., Day, N. large increase in plasma levels of retinol in the placebo group.3 E., Zheng, H. J.. Grassi, A., Li, W. Y., Liu, G. L., Lang, Y. Q.. Zhang, C. Y., Zheng, S. F., Li, J. Y., Correa, P., O'Conor, G. T., and Bosch, F. X. No It is generally accepted that blood retinol levels are homeo- effect of riboflavin, retinol and zinc on prevalence of precancerous lesions of statically controlled within the normal range of vitamin A stores esophagus. Lancet, 2: 111-114, 1985. in the liver, i.e., 20-300 /Â¿g/gliver. Below 20 Mg/g of liver, 11. MuÃ±oz,N., Hayashi, M., Lu, J. B., Wahrendorf, J., Crespi, M., and Bosch, F. X. 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Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1988 American Association for Cancer Research. Blood, Retinol and Zinc Riboflavin Status in Relation to Precancerous Lesions of the Esophagus: Findings from a Vitamin Intervention Trial in the People's Republic of China

Jürgen Wahrendorf, Nubia Muñoz, Lu Jian-Bang, et al.

Cancer Res 1988;48:2280-2283.

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