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Vitamin a serum levels and dietary vitamin a intake in lung cancer patients
Cancer Letters, 4 (1977) 51--54 © Elsevier/North-Holland Scientific Publishers Ltd.
51
VITAMIN A SERUM LEVELS AND DIETARY VITAMIN A INTAKE IN LUNG CANCER PATIENTS
MARTIN H. COHEN, ARON PRIMACK, LAWRENCE E. BRODER and LILLIE R. WILLIAMS NCI-VA Medical Oncology Branch, Veterans Administration Hospital, Washington, D.C. 20422 (U.S.A.) (Received 29 August 1977) (Accepted 3 October 1977)
SUMMARY
Clinical and experimental evidence indicates a possible role for vitamin A deficiency in the pathogenesis of bronchogenic carcinoma. We, therefore, measured serum vitamin A levels in 67 newly diagnosed non-resectable lung cancer patients. In 43 of these patients daily vitamin A intake was also determined. Serum vitamin A levels were within the normal range of the general population in 66 of the 67 patients. Eighteen of 43 patients had daily vitamin A intakes less than 5000 IU/day while 25 patients had daily intake above this level. The serum vitamin A level did not correlate with histologic subtype, extent of disease or presence or absence of hepatic metastases. While these data suggest that vitamin A deficiency was not implicated in pulmonary carcinogenesis; more definitive conclusions await prospective evaluation of high risk individuals followed serially for many years.
INTRODUCTION
Vitamin A deficiency may be implicated in the etiology of bronchogenic carcinoma. Thus individuals with inadequate dietary vitamin A intake had an increased incidence of epidermoid and undifferentiated lung cancer when c o m p ~ e d with other persons matched for age, urban/rural residence and cigarette smoking history who had a more normal vitamin intake [2]. Also a recent preliminary clinical report indicates that patients with epidermoid or oat cell carcinoma, but not large cell anaplastic carcinoma, had significantly lower plasma vitamin A levels than did control patients [ l ] . Experimentally, Address for reprints: Martin H. Cohen, M.D., NCI-VA Medical Oncology Branch, Veterans Administration Hospital, 50 Irving Street, N.W. Washington, D.C. 20422, U.S.A.
52 vitamin A deficiency results in an altered respiratory epithelium with decreased numbers of columnar ciliated and mucous secretory cells. Decrease in these normal respiratory elements is associated with the development of squamous metaplasia [ 7,8 ]. Vitamin A de ficiency.is also associated with increased binding of chemical carcinogens to the respiratory epithelium [6]. By contrast, administration of vitamin A is able to reverse metaplasia in vitro [ 4] while systemically administered vitamin A inhibits development of carcinogen induced respiratory neoplasms [5,10]. The implications of the above observations as regards lung cancer prevention ~re obvious. It is important, therefore, to further define possible relationships between vitamin A intake, vitamin A blood levels and the occurrence of the various histologic types of lung cancer. MATERIALS AND METHODS Patients Sixty-seven consecutive, newly diagnosed, histologically proven lung cancer patients (64 males, 3 females) were studied at the Washington, D.C. Veterans Administration Hospital. All patients were non-resectable and had not received prior therapy. Their mean age was 59 years (range 40--83); 75% of patients were Caucasian. They had smoked cigarettes for an average of 30 pack-years. Disease was confined to one hemithorax in 21 patients and was disseminated in the remainder. No patient had lost greater than 10% of his initial body weight in the month preceding hospitalization and no patient was completely bedridden at the time of study. No patient was taking supplemental vitamin A. Vitamin A Serum vitamin A was determined by a modification of the method of Sobel and Snow [11]. Vitamin A was dissociated from protein by warming with ethanolic potassium hydroxide and was extracted into petroleum ether. After evaporation to dryness, the residue was dissolved in chloroform, reacted with glycerol dichlorohydrin and absorbance was measured at 550 and 960 nm. Dietary vitamin A intake The last 43 patients entered on study were questioned by a registered dietitian as to their eating patterns during a 2-week or longer period immediately prior to hospital admission. They also had a pretreatment dietary intake recorded daily for 3 days while in the hospital. Vitamin A content of ingested nutrients was determined from standard tables [3,12]. RESULTS Serum levels of vitamin A in lung cancer patients are listed in Table 1. Serum vitamin A levels fell within the normal range of the test laboratory in 66 of the 67 patients studied. There were no differences in serum vitamin A levels between individuals who had regional or disseminated disease and there was no difference
53 TABLE I S E R U M V I T A M I N A L E V E L S IN L U N G C A N C E R Histologic cell t y p e
Number of patients
Vitamin A u g / 1 0 0 ml
Epidermoid carcinoma Small cell c a r c i n o m a Adenocarcinoma Large cell c a r c i n o m a Control population
23 19 15 10 --
58 58 58 50 50
+ 16 a + 15 + 17 -+ 12 -+ 20
a Mean _+ S.D.
in serum vitamin A levels whether metastatic disease to the liver was present or not. Average daily caloric intake was similar for the patient's hospital diet as compared to his home diet. Six patients had a daffy caloric intake between 1000 and 1500 kcal/day while the remaining patients ingested more than 1500 kcal/day. Vitamin A intake generally correlated with total caloric intake, with the main source of vitamin being whole milk, milk products and eggs. Vegetables were a minor source of vitamin A intake in most patients. Using 5000 IU of vitamin A as a recommended daily dietary allowance, 18 patients (42%) had intakes below this level. The median daily intake in these 18 patients was 2900 IU (range 1644--4600 IU). Twenty-five patients ingested more than 5000 IU/day. Median intake for these patients was 10,600 IU (range 5500-- 22,700 IU}. Despite these considerable differences in vitamin A ingestion, all 43 of these patients had serum vitamin A levels within the normal range. DISCUSSION
As indicated earlier, two reports support the hypothesis that vitamin A deficiency predisposes to certain histologic types of lung cancer [1,2]. One study evaluated daily dietary vitamin ingestion while the other evaluated serum vitamin A levels in lung cancer patients vs. a control population. In the present study both the serum level of vitamin A and the daily dietary intake of this vitamin were determined in newly diagnosed patients. In 25 of 43 patients giving dietary histories, vitamin A intake both at home and in the hospital exceeded the recommended daily dietary allowance of 5000 IU/day for this vitamin while in 18 individuals vitamin intake was less than the recommended allowance. All 43 patients, however, had serum vitamin A levels within the normal range although patients with greater vitamin A intakes tended to have higher serum levels. In all, 66 of 67 patients with biopsy proven lung cancer had a normal serum vitamin A analysis. There was no difference in serum vitamin A levels by histologic cell type. This differs from the results of Basu et al. [1] who found significantly lower plasma vitamin A levels in subjects with epidermoid and small cell carcinoma as compared to value for patients with
54 large cell anaplastic c a r c i n o m a . P r e s u m a b l y m a n y f a c t o r s a c c o u n t f o r the o b s e r v e d d i f f e r e n c e s including d i e t a r y p r e f e r e n c e s , caloric i n t a k e and general s t a t e o f h e a l t h o f t h e s t u d y patients. A d e f i c i e n c y o f all clinical studies, including the p r e s e n t r e p o r t , relating v i t a m i n A d e f i c i e n c y t o p u l m o n a r y carcinogenesis is the f a c t t h a t v i t a m i n A s e r u m levels or d i e t a r y i n t a k e is d e t e r m i n e d o n l y o n c e , usually during a t i m e p e r i o d s h o r t l y b e f o r e or s h o r t l y a f t e r diagnosis o f lung cancer. Since p u l m o n a r y carcinogenesis is a c h r o n i c p r o c e s s o c c u p y i n g m a n y y e a r s [9] it is p r o b a b l y n e c e s s a r y t o d e t e r m i n e v i t a m i n A status f o r the entire t i m e period. I n o u r p a t i e n t s we f e l t t h a t d i e t a r y histories f o r a 1 0 - y e a r o r longer p e r i o d w e r e t o o u n r e l i a b l e t o be useful. S t o r e d s e r u m was also n o t available. T o c o n c l u s i v e l y d e t e r m i n e if a r e l a t i o n s h i p exists b e t w e e n v i t a m i n A d e f i c i e n c y and lung c a n c e r d e v e l o p m e n t it is n e c e s s a r y t o d e t e r m i n e s e r u m v i t a m i n A levels a n d d i e t a r y v i t a m i n A ingestion serially in high risk individuals being f o l l o w e d at 4 - - 6 m o n t h intervals in lung c a n c e r screening trials. S u c h trials, if p r o p e r l y designed, m i g h t also address the q u e s t i o n as t o w h e t h e r v i t a m i n A s u p p l e m e n t a t i o n , as d o n e in e x p e r i m e n t a l carcinogenesis studies [ 4 , 5 , 1 0 ] , m i g h t d e l a y or p r e v e n t t h e d e v e l o p m e n t o f p u l m o n a r y neoplasia. REFERENCES 1 Basu, T.K., Donaldson, D., Jenner, M., Williams, D.C. and Sakula, A. (1976) Plasma vitamin A in patients with bronchial carcinoma. Br. J. Cancer, 33, 119--121. 2 Bjelke, E. (1975) Dietary vitamin A and human lung cancer. Int. J. Cancer, 15,561-565. 3 Church, C.F. and Church, H.N. (1975) Food Values of Portions Commonly Used. Lippincott, Philadelphia. 4 Clamon, G.H., Sporn, M.B., Smith, J.M. and Saffiotti, U. (1974) a and ~-retinyl acetate reverse metaplasias of vitamin A deficiency in hamster trachea in organ culture. Nature (London), 250, 64--66. 5 Cone, M.V. and Nettesheim, P. (1973) Effects of vitamin A on 3-methyl-cholanthrene induced squamous metaplasias and early tumors in the respiratory tract of rats. J. Natl. Cancer Inst., 50, 1599--1606. 6 Genta, V.M., Kaufman, D.G., Harris, C.C., Smith, J.M., Sporn, M.B. and Saffiotti, U. (1974) Vitamin A deficiency enhances binding of benzo(a)pyrene to tracheal epithelial DNA. Nature (London), 247, 48--49. 7 Harris, C.C., Sporn, M.B., Kaufman, D.G., Smith, J.M., Jackson, F.E. and Saffiotti, U. (1972) Histogenesis of squamous metaplasia in the hamster tracheal epithelium caused by vitamin A deficiency or benzo(a)pyrene-ferric oxide. J. Natl. Cancer Inst., 48,743-761. 8 Harris, C.C. (1974) Cause and prevention of lung cancer. Semin. Oncol., 1,163--166. 9 Saccomanno, G., Archer, V.E., Auerbach, O., Saunders, R.P. and Brennan, L.M. (1974) Development of carcinoma of the lung as reflected in exfoliated cells. Cancer, 38,256-270. 10 Saffiotti, U., Montesano, R., Sellakumar, A.R. and Borg, S.A. (1967) Experimental cancer of the lung. Inhibition by vitamin A of the induction of tracheohronchial squamous metaplasia and squamous cell tumor. Cancer, 20,857--864. 11 Sobel, A.E. and Snow, S.D. (1947) The estimation of serum vitamin A with activated glycerol dichlorohydrin. J. Biol. Chem., 171,617--632. 12 Watt, B.K. and Merrill, A.L. (1963) Composition of Foods. Agriculture Handbook No. 8, U.S. Department of Agriculture, Washington, D.C.
51
VITAMIN A SERUM LEVELS AND DIETARY VITAMIN A INTAKE IN LUNG CANCER PATIENTS
MARTIN H. COHEN, ARON PRIMACK, LAWRENCE E. BRODER and LILLIE R. WILLIAMS NCI-VA Medical Oncology Branch, Veterans Administration Hospital, Washington, D.C. 20422 (U.S.A.) (Received 29 August 1977) (Accepted 3 October 1977)
SUMMARY
Clinical and experimental evidence indicates a possible role for vitamin A deficiency in the pathogenesis of bronchogenic carcinoma. We, therefore, measured serum vitamin A levels in 67 newly diagnosed non-resectable lung cancer patients. In 43 of these patients daily vitamin A intake was also determined. Serum vitamin A levels were within the normal range of the general population in 66 of the 67 patients. Eighteen of 43 patients had daily vitamin A intakes less than 5000 IU/day while 25 patients had daily intake above this level. The serum vitamin A level did not correlate with histologic subtype, extent of disease or presence or absence of hepatic metastases. While these data suggest that vitamin A deficiency was not implicated in pulmonary carcinogenesis; more definitive conclusions await prospective evaluation of high risk individuals followed serially for many years.
INTRODUCTION
Vitamin A deficiency may be implicated in the etiology of bronchogenic carcinoma. Thus individuals with inadequate dietary vitamin A intake had an increased incidence of epidermoid and undifferentiated lung cancer when c o m p ~ e d with other persons matched for age, urban/rural residence and cigarette smoking history who had a more normal vitamin intake [2]. Also a recent preliminary clinical report indicates that patients with epidermoid or oat cell carcinoma, but not large cell anaplastic carcinoma, had significantly lower plasma vitamin A levels than did control patients [ l ] . Experimentally, Address for reprints: Martin H. Cohen, M.D., NCI-VA Medical Oncology Branch, Veterans Administration Hospital, 50 Irving Street, N.W. Washington, D.C. 20422, U.S.A.
52 vitamin A deficiency results in an altered respiratory epithelium with decreased numbers of columnar ciliated and mucous secretory cells. Decrease in these normal respiratory elements is associated with the development of squamous metaplasia [ 7,8 ]. Vitamin A de ficiency.is also associated with increased binding of chemical carcinogens to the respiratory epithelium [6]. By contrast, administration of vitamin A is able to reverse metaplasia in vitro [ 4] while systemically administered vitamin A inhibits development of carcinogen induced respiratory neoplasms [5,10]. The implications of the above observations as regards lung cancer prevention ~re obvious. It is important, therefore, to further define possible relationships between vitamin A intake, vitamin A blood levels and the occurrence of the various histologic types of lung cancer. MATERIALS AND METHODS Patients Sixty-seven consecutive, newly diagnosed, histologically proven lung cancer patients (64 males, 3 females) were studied at the Washington, D.C. Veterans Administration Hospital. All patients were non-resectable and had not received prior therapy. Their mean age was 59 years (range 40--83); 75% of patients were Caucasian. They had smoked cigarettes for an average of 30 pack-years. Disease was confined to one hemithorax in 21 patients and was disseminated in the remainder. No patient had lost greater than 10% of his initial body weight in the month preceding hospitalization and no patient was completely bedridden at the time of study. No patient was taking supplemental vitamin A. Vitamin A Serum vitamin A was determined by a modification of the method of Sobel and Snow [11]. Vitamin A was dissociated from protein by warming with ethanolic potassium hydroxide and was extracted into petroleum ether. After evaporation to dryness, the residue was dissolved in chloroform, reacted with glycerol dichlorohydrin and absorbance was measured at 550 and 960 nm. Dietary vitamin A intake The last 43 patients entered on study were questioned by a registered dietitian as to their eating patterns during a 2-week or longer period immediately prior to hospital admission. They also had a pretreatment dietary intake recorded daily for 3 days while in the hospital. Vitamin A content of ingested nutrients was determined from standard tables [3,12]. RESULTS Serum levels of vitamin A in lung cancer patients are listed in Table 1. Serum vitamin A levels fell within the normal range of the test laboratory in 66 of the 67 patients studied. There were no differences in serum vitamin A levels between individuals who had regional or disseminated disease and there was no difference
53 TABLE I S E R U M V I T A M I N A L E V E L S IN L U N G C A N C E R Histologic cell t y p e
Number of patients
Vitamin A u g / 1 0 0 ml
Epidermoid carcinoma Small cell c a r c i n o m a Adenocarcinoma Large cell c a r c i n o m a Control population
23 19 15 10 --
58 58 58 50 50
+ 16 a + 15 + 17 -+ 12 -+ 20
a Mean _+ S.D.
in serum vitamin A levels whether metastatic disease to the liver was present or not. Average daily caloric intake was similar for the patient's hospital diet as compared to his home diet. Six patients had a daffy caloric intake between 1000 and 1500 kcal/day while the remaining patients ingested more than 1500 kcal/day. Vitamin A intake generally correlated with total caloric intake, with the main source of vitamin being whole milk, milk products and eggs. Vegetables were a minor source of vitamin A intake in most patients. Using 5000 IU of vitamin A as a recommended daily dietary allowance, 18 patients (42%) had intakes below this level. The median daily intake in these 18 patients was 2900 IU (range 1644--4600 IU). Twenty-five patients ingested more than 5000 IU/day. Median intake for these patients was 10,600 IU (range 5500-- 22,700 IU}. Despite these considerable differences in vitamin A ingestion, all 43 of these patients had serum vitamin A levels within the normal range. DISCUSSION
As indicated earlier, two reports support the hypothesis that vitamin A deficiency predisposes to certain histologic types of lung cancer [1,2]. One study evaluated daily dietary vitamin ingestion while the other evaluated serum vitamin A levels in lung cancer patients vs. a control population. In the present study both the serum level of vitamin A and the daily dietary intake of this vitamin were determined in newly diagnosed patients. In 25 of 43 patients giving dietary histories, vitamin A intake both at home and in the hospital exceeded the recommended daily dietary allowance of 5000 IU/day for this vitamin while in 18 individuals vitamin intake was less than the recommended allowance. All 43 patients, however, had serum vitamin A levels within the normal range although patients with greater vitamin A intakes tended to have higher serum levels. In all, 66 of 67 patients with biopsy proven lung cancer had a normal serum vitamin A analysis. There was no difference in serum vitamin A levels by histologic cell type. This differs from the results of Basu et al. [1] who found significantly lower plasma vitamin A levels in subjects with epidermoid and small cell carcinoma as compared to value for patients with
54 large cell anaplastic c a r c i n o m a . P r e s u m a b l y m a n y f a c t o r s a c c o u n t f o r the o b s e r v e d d i f f e r e n c e s including d i e t a r y p r e f e r e n c e s , caloric i n t a k e and general s t a t e o f h e a l t h o f t h e s t u d y patients. A d e f i c i e n c y o f all clinical studies, including the p r e s e n t r e p o r t , relating v i t a m i n A d e f i c i e n c y t o p u l m o n a r y carcinogenesis is the f a c t t h a t v i t a m i n A s e r u m levels or d i e t a r y i n t a k e is d e t e r m i n e d o n l y o n c e , usually during a t i m e p e r i o d s h o r t l y b e f o r e or s h o r t l y a f t e r diagnosis o f lung cancer. Since p u l m o n a r y carcinogenesis is a c h r o n i c p r o c e s s o c c u p y i n g m a n y y e a r s [9] it is p r o b a b l y n e c e s s a r y t o d e t e r m i n e v i t a m i n A status f o r the entire t i m e period. I n o u r p a t i e n t s we f e l t t h a t d i e t a r y histories f o r a 1 0 - y e a r o r longer p e r i o d w e r e t o o u n r e l i a b l e t o be useful. S t o r e d s e r u m was also n o t available. T o c o n c l u s i v e l y d e t e r m i n e if a r e l a t i o n s h i p exists b e t w e e n v i t a m i n A d e f i c i e n c y and lung c a n c e r d e v e l o p m e n t it is n e c e s s a r y t o d e t e r m i n e s e r u m v i t a m i n A levels a n d d i e t a r y v i t a m i n A ingestion serially in high risk individuals being f o l l o w e d at 4 - - 6 m o n t h intervals in lung c a n c e r screening trials. S u c h trials, if p r o p e r l y designed, m i g h t also address the q u e s t i o n as t o w h e t h e r v i t a m i n A s u p p l e m e n t a t i o n , as d o n e in e x p e r i m e n t a l carcinogenesis studies [ 4 , 5 , 1 0 ] , m i g h t d e l a y or p r e v e n t t h e d e v e l o p m e n t o f p u l m o n a r y neoplasia. REFERENCES 1 Basu, T.K., Donaldson, D., Jenner, M., Williams, D.C. and Sakula, A. (1976) Plasma vitamin A in patients with bronchial carcinoma. Br. J. Cancer, 33, 119--121. 2 Bjelke, E. (1975) Dietary vitamin A and human lung cancer. Int. J. Cancer, 15,561-565. 3 Church, C.F. and Church, H.N. (1975) Food Values of Portions Commonly Used. Lippincott, Philadelphia. 4 Clamon, G.H., Sporn, M.B., Smith, J.M. and Saffiotti, U. (1974) a and ~-retinyl acetate reverse metaplasias of vitamin A deficiency in hamster trachea in organ culture. Nature (London), 250, 64--66. 5 Cone, M.V. and Nettesheim, P. (1973) Effects of vitamin A on 3-methyl-cholanthrene induced squamous metaplasias and early tumors in the respiratory tract of rats. J. Natl. Cancer Inst., 50, 1599--1606. 6 Genta, V.M., Kaufman, D.G., Harris, C.C., Smith, J.M., Sporn, M.B. and Saffiotti, U. (1974) Vitamin A deficiency enhances binding of benzo(a)pyrene to tracheal epithelial DNA. Nature (London), 247, 48--49. 7 Harris, C.C., Sporn, M.B., Kaufman, D.G., Smith, J.M., Jackson, F.E. and Saffiotti, U. (1972) Histogenesis of squamous metaplasia in the hamster tracheal epithelium caused by vitamin A deficiency or benzo(a)pyrene-ferric oxide. J. Natl. Cancer Inst., 48,743-761. 8 Harris, C.C. (1974) Cause and prevention of lung cancer. Semin. Oncol., 1,163--166. 9 Saccomanno, G., Archer, V.E., Auerbach, O., Saunders, R.P. and Brennan, L.M. (1974) Development of carcinoma of the lung as reflected in exfoliated cells. Cancer, 38,256-270. 10 Saffiotti, U., Montesano, R., Sellakumar, A.R. and Borg, S.A. (1967) Experimental cancer of the lung. Inhibition by vitamin A of the induction of tracheohronchial squamous metaplasia and squamous cell tumor. Cancer, 20,857--864. 11 Sobel, A.E. and Snow, S.D. (1947) The estimation of serum vitamin A with activated glycerol dichlorohydrin. J. Biol. Chem., 171,617--632. 12 Watt, B.K. and Merrill, A.L. (1963) Composition of Foods. Agriculture Handbook No. 8, U.S. Department of Agriculture, Washington, D.C.