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Ketchup and Cervical Cancer:

Jacob Schor ND, FABNO

June 6, 2010

An interesting study was published earlier this year that has me encouraging our daughter to eat more ketchup on her food.

The study was on cervical cancer and looked at the risk of being diagnosed with this type of cancer and how it related to diet, particularly at several micronutrients in the diet.  Cervical cancer is relatively rare in the United States; about 11,270 cases were diagnosed in the US in 2009 and was responsible for 4,070 deaths.

Internationally the situation is quite different. “Cervical cancer is the third most common cancer worldwide, and 80% of cases occur in the developing world. It is the leading cause of death from cancer among women in developing countries, where it causes about 190,000 deaths each year.”  

Part of the difference of course is preventive screening.  PAP smears that look for early signs of cervical cancer have been widely adopted in the United States.  Early detection and early treatment of cervical cancer works well in countries that can afford it.  But what about countries that can’t afford these modern interventions.  It appears from this recent study that simply eating better can reduce risk significantly.  And of all things, ketchup.

We had better back up a bit and fill in the details.  The study I’m referring to was published last February in the International Journal of Cancer and written by Tomita et al, team members of the Brazilian Investigation into Nutrition and Cervical Cancer Prevention (BRINCA) Study Team.  They looked for an association between levels of various carotenes and tocopherols in the blood serum of patients with cervical cancer.  Data was collected from 605 low income women newly diagnosed with invasive cervical intraepithelial neoplasia (CIN), grades 1, 2, 3 or invasive cancer who were treated at either of two public health clinics in São Paulo, Brazil between 2003 and 2005. The cases were divided into 4 groups by histological diagnosis (CIN1, n = 140; CIN2, n = 126; CIN3, n = 231; invasive cancer, n =108) and 453 controls.

 

After adjusting for the confounding variables and HPV status, there was a significant inverse relationship between serum lycopene levels and CIN1, CIN2, and cervical cancer when the highest and lowest tertiles of lycopene were compared:

Stage                                          Odds Ratio (95% CI)

CIN1                                          0.53 (0.27-1.00, p for trend = 0.05)

CIN3                                          0.48 (0.22-1.04, p for trend = 0.05)                                         

Invasive Cancer               0.18 (0.06-0.52, p for trend = 0.002)

 

Let me try and explain this in clearer terms.  The women were ranked by the concentration of lycopene in their blood.  Think of how school students are ranked by cumulative grade point averages.  The researchers compared cancer statistics for women who were in the top third of the class, or what they call the upper tertile, against women in the lower third of the ranking.  The researchers express the rate of cervical cancer for these two groups as a ratio, what is called an Odds Ratio.    Thus for example, the Odds Ratio for developing invasive cervical cancer was 0.18.  This ratio can be expressed a number of different ways.  One can say that the group of women with the higher levels of lycopene have a rate of cervical cancer that is 82% lower than the other group. 

 Having greater amounts of lycopene lowered the chance of getting cervical cancer. 

High levels of serum alpha- and gamma-tocopherols, and higher consumption of dark green and deep yellow vegetables/fruit were associated with almost 50% decreased risk of CIN3.

 

We typically assume that cervical cancer is directly caused by infection with human papillomavirus (HPV), but that’s an oversimplification.   It is more accurate to say that infection with, “…. HPV is recognized as being a necessary, but not sufficient, cause of cervical cancer.”   It is not being infected that is the real problem, it is the persistence of the infection that increases risk.   The longer the infection lingers, the more likely that the woman will develop cancer.

 

Persistence of HPV infection depends on a number of factors; older women clear it faster, poorer women clear it slower.  Younger poor women clear it even slower.  This sociodemographic variation in risk may be simply a matter of nutritional status.  The speed of HPV clearance varies with micronutrient status.   If one is nutritionally deficient, the virus lingers longer.  Some studies report t a range of chemicals that are important: “…levels of trans-zeaxanthin, total trans-lutein/zeaxanthin, cryptoxanthin (total and beta), total trans-lycopene and cis-lycopene, carotene (alpha, beta, and total), and total carotenoids were associated with a significant decrease in the clearance time…” But a number of studies others single out particular nutrients, particularly, vitamin A and lycopene, or vitamin E and cryptoxanthin,   lycopene may, in this regard, be the most essential micronutrient. The current study certainly does suggest it is.

Seen in this light, the benefit seen in this Tomita study, is in line with past research.  The magnitude of the protective benefit is still striking.  Risk of CIN 1 and 3 is cut by half.  Risk of invasive cancer is cut by more than 80%.

Cooked tomato products are the best source of dietary lycopene.  Ketchup, particularly the organic products, can be a significant source of lycopene.   Might they also reduce incidence of cervical cancer death?

 

If a food manufacturer wishes to make a health claim on a food package label, then pre-approval by the FDA is required. The FDA published a review paper in 2007 that stated that there was not sufficient evidence to support a label claim that lycopene has a protective effect against long list of cancers.  

 The evidence required to support such a claim is quite stringent. “Eighty-one observational studies examined the relationship between lycopene intake and the risk of prostate, lung, colorectal, gastric, breast, cervical, ovarian, endometrial, or pancreatic cancer, all of which FDA excluded from consideration.” The reason given for exclusion was that, “…none was an interventional study of lycopene intake in subjects who had not been diagnosed with cancer.”

 

The FDA looked at a second sequence of studies and found most were not done to their satisfaction, explaining that, “A total of 64 observational studies of the association between tomato or tomato product consumption and cancer risk were identified.”  Of the 64 studies, 23 were discarded because,  “[they were a ] reanalysis of data that were already used to evaluate the health claim and/or because they had scientific deficiencies that prevented FDA from drawing scientific conclusions from the study.”  From the 39 remaining studies, the FDA was unable to draw firm conclusions.  Our readers are encouraged to review the FDA’s reasoning for discounting these studies first hand. http://jnci.oxfordjournals.org/cgi/content/full/99/14/1074

 

Reading through the material, you will probably find, as I did, that alhough the research may not be strong enough to make label claims, it is more than convincing enough to think, “This won’t hurt and probably will help.”

 

This information should generate a particular rumination on the part of our readers.  The somewhat entertaining thought is whether the relatively low rate of cervical cancer in the United States is really a result of our proactive diagnostic PAP smears or simply the fact that young women at high risk for HPV infection consume a great deal of ketchup. 

 

Related Newsletters from the past:

Tomatoes: the redder the better: http://denvernaturopathic.com/news/lycopene.html

Why buy organic ketchup? http://denvernaturopathic.com/organic.htm

 

References:

 

Int J Cancer. 2010 Feb 1;126(3):703-14.

Diet and serum micronutrients in relation to cervical neoplasia and cancer among low-income Brazilian women.

Tomita LY, Longatto Filho A, Costa MC, Andreoli MA, Villa LL, Franco EL, Cardoso MA; Brazilian Investigation into Nutrition and Cervical Cancer Prevention (BRINCA) Study Team.

Department of Nutrition, School of Public Health, University of São Paulo (USP), São Paulo, SP, Brazil.

Abstract

Cervical cancer is a leading cancer among women in developing countries. Infection with oncogenic human papillomavirus (HPV) types has been recognized as a necessary cause of this disease. Serum carotenoids and tocopherols have also been associated with risk for cervical neoplasia, but results from previous studies were not consistent. We evaluated the association of serum total carotene and tocopherols, and dietary intakes with the risk of newly diagnosed, histologically confirmed cervical intraepithelial neoplasia (CIN) grades 1, 2, 3 and invasive cancer in a hospital-based case-control study in São Paulo, Brazil. The investigation included 453 controls and 4 groups of cases (CIN1, n = 140; CIN2, n = 126; CIN3, n = 231; invasive cancer, n =108) recruited from two major public clinics between 2003 and 2005. Increasing concentrations of serum lycopene were negatively associated with CIN1, CIN3 and cancer, with odds ratios (OR) (95% CI) for the highest compared to the lowest tertile of 0.53 (0.27-1.00, p for trend = 0.05), 0.48 (0.22-1.04, p for trend = 0.05) and 0.18 (0.06-0.52, p for trend = 0.002), respectively, after adjusting for confounding variables and HPV status. Increasing concentrations of serum alpha- and gamma-tocopherols, and higher dietary intakes of dark green and deep yellow vegetables/fruit were associated with nearly 50% decreased risk of CIN3. These results support the evidence that a healthy and balanced diet leading to provide high serum levels of antioxidants may reduce cervical neoplasia risk in low-income women.

PMID: 19642096 [PubMed - indexed for MEDLINE]

http://www.cancer.gov/cancertopics/types/cervical

Int J Cancer. 1999 Sep 24;83(1):18-29.

Estimates of the worldwide mortality from 25 cancers in 1990.

Pisani P, Parkin DM, Bray F, Ferlay J.

Unit of Descriptive Epidemiology, International Agency for Research on Cancer, Lyon, France. pisani@iarc.fr

Reference: Tomita LY, Longatto Filho A, Costa MC, Andreoli MA, Villa LL, Franco EL, Cardoso MA; Brazilian Investigation into Nutrition and Cervical Cancer Prevention (BRINCA) Study Team. Diet and serum micronutrients in relation to cervical neoplasia and cancer among low-income Brazilian women.  Int J Cancer. 2010 Feb 1;126(3):703-14.

J Clin Microbiol. 2008 Feb;46(2):732-9. Epub 2007 Dec 12.

Cervical human papillomavirus (HPV) infection and HPV type 16 antibodies in South African women.

Marais DJ, Constant D, Allan B, Carrara H, Hoffman M, Shapiro S, Morroni C, Williamson AL.

Institute of Infectious Disease and Molecular Medicine and Division of Medical Virology, Department Clinical Laboratory Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town, South Africa. di.marais@uct.ac.za

Abstract

There is a high incidence of cervical cancer in South African women. No large studies to assess human papillomavirus virus (HPV) infection or HPV type 16 (HPV-16) exposure have occurred in the region, a requirement for policy making with regards to HPV screening and the introduction of vaccines. Control women (n = 1,003) enrolled in a case control study of hormonal contraceptives and cervical cancer were tested for 27 cervical HPV types by reverse line blot analysis. The seroprevalence of HPV-16 immunoglobulin G (IgG) and IgA antibodies was assessed by a virus-like particle-based enzyme-linked immunoassay of 908 and 904 control women, respectively, and of 474 women with cervical cancer. The cervical HPV prevalence was 26.1%. The HPV-16 IgG seroprevalence was 44.4% and the HPV-16 IgA seroprevalence was 28.7% in control women, and these levels were significantly higher (61.8% and 52.7%, respectively) for women with cervical cancer (odds ratio [OR], 2.1 and 2.8, respectively). The cervical HPV prevalence showed an association with cervical disease, and the HPV-16 IgG prevalence decreased while the HPV-16 IgA prevalence increased with increasing age (P < 0.05). The prevalence of oncogenic HPV types (including HPV-16) decreased with age, whereas nononcogenic HPV types showed limited association with age. Multivariate analysis revealed cervical HPV infection to be associated with herpes simplex virus type 2 infection (OR, 1.7) and increasing years of education (OR, 1.9). HPV-16 IgG antibodies were inversely associated with current smoking status (OR, 0.6), and the presence of HPV-16 IgA antibodies was inversely associated with the use of alcohol (OR, 2.1) and inversely associated with the use of oral contraceptives (OR, 0.6). High levels of exposure to HPV, and particularly HPV-16, were evident in this population. The apparent increase of serum HPV-16 IgA with increasing age requires further investigation.

J Natl Cancer Inst. 2010 Mar 3;102(5):315-24. Epub 2010 Feb 15.

Longitudinal study of human papillomavirus persistence and cervical intraepithelial neoplasia grade 2/3: critical role of duration of infection.

Rodríguez AC, Schiffman M, Herrero R, Hildesheim A, Bratti C, Sherman ME, Solomon D, Guillén D, Alfaro M, Morales J, Hutchinson M, Katki H, Cheung L, Wacholder S, Burk RD.

Proyecto Epidemiológico Guanacaste, Fundación INCIENSA, Torre La Sabana, 7mo piso, Sabana Norte, San José 10203, Costa Rica. acrodriguez@racsa.co.cr

Abstract

BACKGROUND: The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women's age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease. METHODS: At enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5-7 years (passively followed), whereas higher-risk participants (n = 2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction-based method. We determined, by four age groups (18-25, 26-33, 34-41, and > or =42 years), the proportion of prevalent infections (found at baseline) and newly detected infections (first found during follow-up) that persisted at successive 1-year time points and calculated absolute risks of CIN 2 and CIN grade 3 (CIN 3) or worse during follow-up. P values are two-sided. RESULTS: Regardless of the woman's age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease. For newly detected infections, the rate of progression to CIN 2+ (or CIN 3+), after 3 years of follow-up, was not higher for women aged 34 years and older than for younger women. Moreover, rates of newly detected infections declined sharply with age (in the actively followed group, at ages 18-25, 26-33, 34-41, and > or =42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P < .001). Among prevalent infections, persistent infections among older women (> or =42 years) was higher than that among younger age groups or new infections at any age (P < .01 for comparison of eight groups). Most (66 of 85) CIN 2 or worse detected during follow-up was associated with prevalent infections. Only a small subset (25 of 1128) of prevalent infections persisted throughout follow-up without apparent CIN 2 or worse. CONCLUSIONS: The rate of new infections declines with age, and new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low.

Cancer Res. 2007 Jun 15;67(12):5987-96. Epub 2007 Jun 6.

Hawaii cohort study of serum micronutrient concentrations and clearance of incident oncogenic human papillomavirus infection of the cervix.

Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Franke AA, Bertram CC, Kessel B, Bernice M, Sunoo C, Ning L, Easa D, Killeen J, Kamemoto L, Hernandez BY.

Cancer Research Center of Hawaii, University of Hawaii, HI 96813, USA. marc@crch.hawaii.edu

Abstract

The degree to which the resolution of human papillomavirus (HPV) infection parallels exposure to other factors, particularly those related to nutritional status, is a relatively unexplored area of research. We established a cohort of women for long-term follow-up to examine the association of serum retinol, carotenoid, and tocopherol concentrations with the clearance of incident cervical HPV infection. Interviews and biological specimens were obtained at baseline and at 4-month intervals. At each visit, a cervical cell specimen for HPV DNA analysis and cytology and a fasting blood sample to measure micronutrient levels were collected. A Cox proportional hazards model was used to study the relationship between clearance of 189 incident (type-specific) oncogenic HPV infections and the levels of 20 serum micronutrients among 122 women. Higher circulating levels of trans-zeaxanthin, total trans-lutein/zeaxanthin, cryptoxanthin (total and beta), total trans-lycopene and cis-lycopene, carotene (alpha, beta, and total), and total carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (<or=120 days). HPV clearance time was also significantly shorter among women with the highest compared with the lowest serum levels of alpha-tocopherol and total-tocopherol, but significant trends in these associations were limited to infections lasting <or=120 days. Clearance of persistent HPV infection (lasting >120 days) was not significantly associated with circulating levels of carotenoids or tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.

PMID: 17553901 [PubMed - indexed for MEDLINE]

Cancer Epidemiol Biomarkers Prev. 2002 Sep;11(9):876-84.

Vitamin A, carotenoids, and risk of persistent oncogenic human papillomavirus infection.

Sedjo RL, Roe DJ, Abrahamsen M, Harris RB, Craft N, Baldwin S, Giuliano AR.

Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.

Abstract

Oncogenic human papillomavirus (HPV) infection is the main etiologic factor for cervical neoplasia, although infection alone is insufficient to produce disease. Cofactors such as nutritional factors may be necessary for viral progression to neoplasia. Results from previous studies have suggested that higher dietary consumption and circulating levels of certain micronutrients may be protective against cervical neoplasia. This study evaluated the role of vitamin A and carotenoids on HPV persistence comparing women with intermittent and persistent infections. As determined by the Hybrid Capture II system, oncogenic HPV infections were assessed at baseline and at approximately 3 and 9 months postbaseline. Multivariate logistic regression analysis was used to determine the risk of persistent HPV infection associated with each tertile of dietary and circulating micronutrients. Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence (adjusted odds ratio, 0.46; 95% confidence interval, 0.21-0.97). Also, a 56% reduction in HPV persistence risk was observed in women with the highest plasma cis-lycopene concentrations compared with women with the lowest plasma cis-lycopene concentrations (adjusted odds ratio, 0.44; 95% confidence interval, 0.19-1.01). These data suggest that vegetable consumption and circulating cis-lycopene may be protective against HPV persistenc

Asian Pac J Cancer Prev. 2000;1(3):227-235.

The Association of Plasma Micronutrients with the Risk of Cervical Atypical Squamous Cells of Undetermined Significance (ASCUS).

Goodman MT, McDuffie K, Hernandez B, Hankin JH, Wilkens LR, Franke AA, Kolonel LN, Kuypers J, Kiviat N, Bertram CC, Kessel B, Sunoo C, Nakamura J, Killeen J.

Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, HI 96813, USA. marc@crch.hawaii.edu

Abstract

Little is known about factors that favor the development of cervical atypical squamous cells of undetermined significance (ASCUS), nor how these factors might affect the pathogenesis of cervical neoplasia. The primary focus of this case-control study among the multiethnic population of Hawaii was to identify biomarkers of diet in the recent past that may influence the risk of ASCUS, after carefully accounting for the presence of HPV DNA. Cases included 185 women with ASCUS and 191 cytologically-normal controls diagnosed between 1992 and 1996 from three clinics in Honolulu, Hawaii. In-person interviews were conducted in the subjects' homes, a fasting blood sample was drawn to measure plasma levels of various micronutrients, and the presence and type of HPV was determined in exfoliated cell samples using Polymerase Chain Reaction (PCR) dot blot hybridization. As results, we found an inverse dose-response gradient with increasing plasma concentrations of &mgr;-cryptoxanthin and &mgr;-tocopherol for the development of ASCUS. The odds ratio for ASCUS among women in the highest quartile compared with women in the lowest quartile of total cryptoxanthin was 0.5 (95% confidence interval (CI): 0.3-1.0), &mgr;-cryptoxanthin was 0.4 (0.2-0.8), total tocopherol was 0.5 (0.2-1.0), &mgr;-tocopherol was 0.5 (0.2-1.0), and &mgr;-tocopherol was 0.4 (0.2-0.8). Little association of plasma levels of lutein/zeaxanthin, lycopene, &mgr;- or &mgr;-carotene, retinol, vitamin C, or cholesterol, with disease risk was evident. Our findings suggest that women with high circulating concentrations of cryptoxanthin and tocopherol may be at a reduced risk of ASCUS.

Cancer Causes Control. 2003 May;14(4):319-26.

Effect of plasma micronutrients on clearance of oncogenic human papillomavirus (HPV) infection (United States).

Sedjo RL, Papenfuss MR, Craft NE, Giuliano AR.

Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724-5024, USA.

Abstract

OBJECTIVE: Data have suggested that higher levels of nutrients are protective against HPV persistence and cervical neoplasia. This study assessed the role of circulating nutrients on clearance of oncogenic HPV infections. METHODS: Women were followed prospectively with visits at baseline and approximately 4- and 10-months post-baseline. At each visit, 15 oncogenic HPV types were determined. Plasma levels were assessed at the 4-month visit for retinol, carotenoids (i.e., alpha-, trans-beta-, cis-beta-carotene, alpha-, beta-cryptoxanthin, lutein, zeaxanthin, trans- and cis-lycopene), tocopherols (i.e., alpha-, delta-, and gamma-tocopherol), folate and vitamin B12. Using multivariate Cox proportional hazards models, time to clearance analyses of oncogenic HPV infections were conducted for 84 women with at least one oncogenic infection at baseline. Hazard ratios (HR) were estimated for the association of HPV clearance to each nutrient tertile and to determine linear trends. RESULTS: The likelihood of clearing an oncogenic HPV infection was significantly higher with increasing levels of trans-lycopene (p for trend, 0.025) and cis-lycopene (p for trend, 0.010). The adjusted hazard ratios of the highest tertiles of trans- and cis-lycopene were 2.79 (95% CI = 1.17-6.66) and 2.92 (95% CI = 1.28-6.63) compared with the lowest tertiles. CONCLUSIONS: Higher concentrations of trans- and cis-lycopene may reduce the time to clearance of an oncogenic HPV infection.

PMID: 12846362

J Agric Food Chem. 2004 Dec 29;52(26):8017-20.

A comparison of carotenoid content and total antioxidant activity in catsup from several commercial sources in the United States.

Ishida BK, Chapman MH.

Western Regional Research Center, U.S. Department of Agriculture, Agricultural Research Service, 800 Buchanan Street, Albany, California 94710, USA. bkishida@pw.usda.gov

Abstract

Samples of catsup from 13 commercial sources, representing at least 10 U.S. manufacturers, were analyzed for carotenoid content, antioxidant activity, and percentage solids. The solids content of these catsup brand samples varied from 26.31 to 38.06% solids. The lycopene content ranged from 59.42 to 183.36 microg, and total carotenoids were as high as 216.6 microg/g fresh weight, respectively. In addition, both hydrophilic and lipophilic antioxidant activities were measured using the Trolox equivalent antioxidant capacity (TEAC) assay. These measurements of samples of the various catsup brands ranged from 176.5 to 356.8 total TEAC units.

PMID: 15612790 [Pub

J Natl Cancer Inst. 2007 Jul 18;99(14):1074-85. Epub 2007 Jul 10.

The U.S. Food and Drug Administration's evidence-based review for qualified health claims: tomatoes, lycopene, and cancer.

Kavanaugh CJ, Trumbo PR, Ellwood KC.

RD, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, HFS-830, 5100 Paint Branch Parkway, College Park, MD 20740, USA. claudine.kavanaugh@fda.hhs.gov

Comment in:

Abstract

Several studies have reported an inverse association between tomato and/or lycopene intake and the risk of some types of cancer. In 2004, the U.S. Food and Drug Administration (FDA) received two petitions for qualified health claims regarding tomatoes, lycopene, and the risk reduction for some forms of cancer. Health claims that characterize the relationship between a food or food component and a disease or health-related condition require premarket approval by FDA to be included on the labels of conventional foods and dietary supplements. Here we describe FDA's review of the scientific data for tomato and/or lycopene intake with respect to risk reduction for certain forms of cancer. The FDA found no credible evidence to support an association between lycopene intake and a reduced risk of prostate, lung, colorectal, gastric, breast, ovarian, endometrial, or pancreatic cancer. The FDA also found no credible evidence for an association between tomato consumption and a reduced risk of lung, colorectal, breast, cervical, or endometrial cancer. The FDA found very limited evidence to support an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.