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LYCOPENES and TOMATOES and CANCER

Abstract:  The regular eating of tomato products of the equivalent of one medium sized tomato per day should reduce over sufficient time a probable risk of most or all types of cancer by 43% vs. the risk of  a non-consumer of tomato products.  This action taken regularly can add more than 2 years of Well-Days to the potential life of an average US 50 year old man or woman that now consumes no tomato products. This benefit appears derived from the high lycopene content of the tomato that is not provided similarly in other foods.  Life Ahead shows for any entered diet a deficiency in lycopene in addition to any deficiencies of up to 19 other key nutrients and identifies alternative diet changes needed to reduce the related risk to target levels.

One of the more fascinating recent research findings is that an adequate eating of tomatoes and tomato products that include lycopene can reduce the risk of suffering and dying from cancer.  The Life Ahead global analysis that follows shows that a reasonably moderate intake of tomato products may cut risk of all kinds of cancer in half.  In fact, no other known single dietary health action may be able to provide the cancer protection possible from the eating of tomato products.  Although there has been quite a bit of publicity that eating tomatoes can reduce risk of prostate and some other cancer, few people today - and this includes researchers, nutritionists, doctors, and writers of health books - seem to be clearly aware of the global importance of this. 

A landmark review of this subject was published in a paper by Dr. Edward Giovannucci in 1999 (J Natl Cancer Inst 91:317).  57 of a remarkably large number of 72 studies confirmed cancer benefits for higher tomato intake or lycopene blood levels.  About half of the studies found reduced risks of cancer of 40%.  This  brought what was a sleeping giant out of the closet and into serious public view. Yet as for most medical reviews this analysis involved a study by study citation of results that provided a very conservative picture of likely tomato and lycopene benefits. The Life Ahead global review suggests that nearly all of the included studies that did not confirm benefits really failed to reach 'statistical significance' because of their large margins of error. The actual study by study risks for tomatoes and lycopene are not included herein as are those for most other Life Ahead factors analyzed.  This is because these extensive actual data are similarly presented in Dr. Giovanni's impressive paper that is available free on NIH's Medline internet site.  http://jncicancerspectrum.oupjournals.org/cgi/content/full/jnci;91/4/317

But health-interested persons want to know further (1) What and how much meaningful health benefit can be provided by the eating of tomato products;  (2)  How much of what kinds of products they need to eat;   (3)  How sure can we be that these benefits are real.  (4)  Is this mostly just another confirmation that eating fruits and vegetables is good for health?  The Life Ahead statistical and global analysis that answers these questions follows.  Those not interested in these technical details can jump over to the next section

The Global Analysis of Lycopene and Tomato Health Benefits:  A key problem in reaching a probable truth from a series of population health studies is their usual wide margin of possible error.  A typical health study showing a risk factor of say 0.70 will have a 5%-95% error margin of from about 0.4 to 1.0.  Results in the media and those used in most summary medical reviews tend to highlight the value of 0.7, but overlook the fact that the study really only identified a risk probably somewhere between a useful  0.4 and a non-useful 1.0. Consider two studies of prostate cancer, study Nomura with risk of 1.1 (5-95% range 0.5-2.2) and Cerhan, risk 0.5 (range 0.3 to 0.9).  These usually are cited as in disagreement, with one denying a benefit, and the other showing a benefit. This is misleading. The statistical error values reveal that twenty Nomura type studies probably would develop a series of values 18 of which would range between 0.5 and 2.2, and two would fall outside this range.  Eighteen of  20 of Cerhan type study results would similarly fall between 0.3 and 0.9.  Values from 0.6 to 0.9 would be found determined from each study series.  Thus within their recognized statistical limits, these two study results are 'statistically consistent' with a likely risk value between about 0.6 and 0.9 within their recognized margins of error.  If the 5-95% range of differing studies embrace the same value, their results are statistically consistent.  Their results thus are within an expected statistical pattern, are consistent and do not disagree.  The above review of tomato and lycopene benefits found 82 researched comparisons that included study margins of error.  68 of these were statistically consistent with a probable risk benefit of cancer of about 0.6, or a 40% reduction in risk.  8 found a somewhat higher benefit than this 40% reduction, and only 6 found a somewhat lower benefit. This variation is nearly just that expected from known study margins of error for a risk factor of 0.6.  

A meta analysis attempts to penetrate this statistical confusion further by developing a most probable average risk from all available studies. A global analysis that should be still more meaningful relates the risk from all studies to probable causative factors.  To accomplish this, a data base of 44 studies was developed from Giovannucci's tables that included both risk ratio values of cancer and either approximate differences in number of tomatoes eaten per day, and differences in amount of lycopene eaten each day.  Because lycopene values were mostly estimated from tomato products eaten, these values are largely interdependent.  A value of 3400 mcg of lycopene was taken for one average tomato where needed. 

The results of regressions of these data for nine different types of cancer included were:

 (1) For tomatoes eaten:

      Risk Ratio = Exp( -0.5546 * number tomatoes/day)             t of coefficient 8.11,  r=0.79

(2) For lycopene:

     Risk Ratio = Exp( -0.00015 * lycopene in mcg/day)              t of coefficient 8.46,  r= 0.78

In more familiar terms these results show a log mean risk ratio for cancer of 0.57 (5-95% limits 0.50 to 0.66) for the eating of one tomato equivalent per day vs. eating no tomato products.  With the resolving power included of 44 different study results the statistical limits are remarkably narrow.  The 't' values of 8+ compare with the value of only 2 needed for 95% significance. Compared with a 43% most probable reduction in cancer risk, this indicates even at a 95% likelihood a minimum reduction in risk of cancer of 34% is obtained for the eating of just one daily tomato equivalent. Ten of the 44 studies found risk ratios of 0.50 or lower.  It seems quite likely that a cancer risk reduction of 50% is potential from the eating of perhaps 1.5  tomato equivalents per day.  

Another 12 useful studies in the above paper provided risk ratios for populations that had various differences in the amount of lycopene in their blood. The average log mean risk for the higher amounts vs. lower amounts of lycopene was 0.60.  This value is near identical to the 0.57 average found from the research on dietary intake.  Although no adequate translation of the dietary intake values to blood levels was found, the higher amounts of blood values of lycopene in the populations probably were closely related to their higher intake of tomato equivalents eaten.  Thus this provides a direct confirmation that the lycopene content of the tomato products probably was the principal factor that caused the reduction in risk of cancer from the studies of tomato intake. There is further support for this from many of the more than a thousand studies of lycopene now referenced on NIH's Medline site.

In summary, the benefits of tomatoes and lycopene in reducing cancer risk are very well confirmed. The valuation of dose response in the research was essentially nil, and thus the present formula assumes log risk to be proportional to amount of intake. This probably is an approximation.  Another potential problem not answered is how benefits of lycopene add to benefits from other carotenes and antioxidants. For example the proposed pool of four major antioxidants considered in Life Ahead computes a potential cancer risk reduction of up 50%.  No evidence was noted that lycopene benefits were duplicative of this risk, but no good data were found that confirm lycopene benefits as clearly additional to the benefits from these other antioxidants.

The progression of cancer occurs over the decades of a lifetime. For example, about 20 years of exposure from cigarettes is needed for cancer to develop.  (See 'Cancer, a Chemical Process' on the Life Ahead Web site.)  Lycopene probably slows the rate of cancer development.  A major deficiency in most of today's health research is that it relates risk to a snapshot of diet rather than a longer term analysis of former diet.  A usual observation study probably considers population diets that were fairly persistent over 7 to 10 years or longer. This may be a typical exposure time studied today via research.  A study of Hansson (Int J Cancer 55:181) confirmed that cancer risk was related to tomato amounts eaten both in adolescence and during 20 years prior.  Thus an individual that initiates a new diet routine cannot expect that  risk of cancer will be immediately decreased or increased.  The health-interested person must recognize that protection against cancer may develop only gradually and progressively only after many years duration of a changed habit. 

Effect of Tomatoes and Lycopene on Risk of Various types of Cancer:   The table following summarizes the  risks found of various types of cancer from tomato intake.

Interestingly, risks that were verified by 4 or more studies were essentially similar for each cancer site researched. For these four cancer types that comprise about 2/3rds of all cancer deaths the average measured risks were statistically consistent with that for the average of all cancer sites. Although the values for the other sites varied, each still was statistically consistent with the value of 0.57 for all cancer sites.  Although the dietary value for breast cancer showed minimal benefit, the risk from blood measurements from four breast cancer comparisons was similar to that from all studies.

Statistics only can support or not support a given hypothesis. The actual research data now support 100% the hypothesis that the cancer risk related to lycopene and tomatoes is similar or the same for all cancer types. This conclusion of course is tentative because of the limited available data on some sites and will not be appealing to researchers who like to have every site tested extensively.  The opposing hypothesis that cancer risk will vary by site is not now supported with 95% statistical significance by the available results on any cancer site and thus remains as conjecture until sufficient data to the contrary become available. Thus at this time a most likely assumption must be that all cancer types are affected similarly by lycopene.  The health-interested person should recognize this likelihood and not assume he or she has no lycopene related risk of cancer at these less well confirmed sites just because insufficient direct research on them is not yet available.

This concept of possibly similar cancer risks by site by a cause is of large potential importance because it can infer that results obtained on one type may by valid for all or at least nearly all other types. This is not true for the effect of cigarettes that have widely differing effects on lung and other cancers.  But the Life Ahead analysis of Vitamin E found similar effects on differing cancer types tested for Vitamin E.   The effects of exercise and cardiofitness on cancer risk also were closely consistent on the differing cancer types from the 89 different research comparisons analyzed. These analyses all are provided on the Life Ahead Web Site.  (http://members.cox.net/forrestx/)  Cancer progresses slowly during life via some biological process, and vitamins and Lycopene and other factors appear to slow this progress by perhaps a cumulating 2-4% each year. Such a rate of slowing could apply similarly to its eventual eruption at any site.  In contrast, cancer produced by a carcinogen such as a tar can be strongly related to the specific site affected.

Tomatoes, Lycopene, and Risk of Cardiovascular Disease:  A few studies have indicated that tomatoes and lycopene intake reduces risk of heart and cardiovascular diseases. (Sesso,J Nutr 2003,133:2336 and Am J Clin Nutr 2004, 79:47 and Rissanen, (Br J Nutr 2001, 85:749 and Exp Biol Med, 2002 227:900) .  Sesso from 28,000 women found risk ratios of about 0.7 for both higher blood levels and higher  tomato intake of lycopene with a somewhat uneven dose response.  Rissanen found a high risk for low lycopene levels and also found that lycopene slowed the rate of artery atherosclerosis.  On balance it was felt that current research results are not sufficient for inclusion of a CVD benefit for lycopene in Life Ahead, but this should be followed closely.  But because of these findings and that lycopene is well confirmed as an antioxidant, the present Life Ahead forecast of lycopene health benefits based only on cancer risk benefit may be somewhat conservative.

Lycopene and Tomatoes Provide some Highly Unique Benefits:  There has been widespread publicity recently that "everyone should eat at least 4-5 or more daily portions of fruits and vegetables for health."   There is inference here and that is repeated in some health books that tomatoes are just one of these vegetables.  This is seriously incorrect. 

The available 10 population studies of the direct benefits of fruits and vegetables suggest that each portion of an 'average' fruit or vegetable reduces cardiovascular risk by a risk factor of about 0.93, and reduces cancer risk by a factor of about 0.97.  These average benefit values are closely confirmed by Life Ahead's entirely independent valuation of the benefits expected from fat, vitamin, and other content of groups of 'average' fruits and vegetables. (See "Fruits and Vegetables" on the Life Ahead Site).  The above reduction in cancer risk from just one tomato equivalent per day of 43% compares with only a 3% reduction in cancer risk from an 'other' vegetable.  These benefits hardly are similar or even in the same dimension. It would take intake of 14 other fruits and vegetables each day to reduce cancer as much as will one tomato equivalent.  

Another observation is this:  The research data on tomatoes were developed directly from the actual amounts of tomatoes eaten.  The important research to date on other foods except perhaps nuts was derived from estimated consumption of nutrients as vitamins, minerals, fats etc. in the foods.  There always has been a question about possible nutrients in foods not known that could have contaminated the result for the concerned nutrients.  The research on tomatoes is by far the largest body of available population research yet done directly on any single food per se.

There seems little question from this that there must be something very much different about the tomato. This difference almost certainly is lycopene.  Tomatoes include it.  With the exception of pink (and only pink) grapefruit and watermelon and a few other foods that include a tiny little of it, only tomatoes include a lot of it. The biochemical behavior of lycopene seems somewhat different from the behavior of other antioxidants.

There is another consideration that elevates the importance of adequate tomato and lycopene intake.  The two major disease groups today that cause 75% of population deaths - and thus usually determine our likely longevity- are cardiovascular diseases and cancer.  There has been enormous progress in the research showing how risk of cardiovascular diseases can be reduced.  And Life Ahead computes that well structured programs of diet and diet supplements and exercise should be able to reduce usual cardiovascular risks by well over 90%.  But this same analysis shows that it is difficult to reduce cancer by more than 2/3rds by usual diet and exercise programs other than lycopene. This leaves cancer as the tough risk to fight.  And that the life of the seriously health-interested person who follows Life Ahead advice on other factors is now likely to be terminated by cancer. If tomatoes and lycopene can accomplish a substantial and further reduction in cancer risk, this not only can extend our likely life span, but can pass on that final cause to something less disagreeable.

Life Ahead now computes lifetime risk from a sophisticated year-by -year life cycle computation.  Adding one tomato equivalent every day for life to the diet of an average US man or woman of age 50 that now includes no tomato intake probably will add about 800 Well-Days or 2.2 years to expected healthy days of life. Somewhat larger tomato intake may add about 1000 more Well-Days.

Lycopene provides the key benefits for Tomato Foods:  Most analyses of food benefits consider the value of only one selected included nutrient. This neglects the potential benefits or debits from the many other nutrients in the food. The above analysis also considers only the single nutrient benefit of lycopene.  Life Ahead uniquely values the individual contributions of up to twenty different nutrients of every included food  Thus a question becomes "How much of the benefit from tomato based products comes from lycopene, and how much comes from the other nutrients of tomatoes that include good beta carotene, vitamin C, potassium and zinc, low saturated fat, and some other useful nutrients?" 

The Life Ahead analysis forecasts about 200 Well-Days benefit for a daily eating of a typical tomato food portion from all of these other nutrient values but excluding lycopene.  This is for an average 50 year old using an average base diet without any tomato product included.  Thus  75% of the 800 Well-Days benefit found for the long range health benefit of the tomato appears derived from its lycopene content.

Accomplishing a Needed Reduction in Cancer Risk with Lycopene:  One medium sized tomato includes about 3400 mcg of lycopene.  The Life Ahead 'Good Health' objective is set at this one medium tomato or 3400 mcg of lycopene per day intake level. One and a half more portions of tomato and lycopene probably will provide some more benefit, and should be a target for a health-interested person that has a family history risk of any kind of cancer.  Compared with this, the lycopene content of some popular tomato source foods from US Department of Agriculture data follow:

              Source                                 mcg/day

Tomato soup,1 cup           13,000

Tomato juice,1/2 cup        12,500

Tomato,cooked,1/2 cup        3,600

Tomato,raw,1 medium          3,200

Pizza,avg,1/8th slice        3,000

Ketchup/catsup,1 tblsp       2,500

Tomato sauce,1 tblsp         2,200

There is no assurance that each of these foods will contribute to health exactly in accord with their measured lycopene content.  Some research suggests that cooking enhances the effectiveness of lycopene, and that raw tomatoes may provide less actually absorbed lycopene than that estimated from its measured content. A small study found less benefit from tomato juice than expected, and high benefit from tomato sauces.  Yet the actual results on cancer risk from Giovannucci's summarized 72 studies found benefits from all types of tomato products.  Because there may be differences in the benefits from the differing products, its seems prudent to obtain our lycopene intake from eating a combination of tomato products.  Because most people find eating most or all of these products enjoyable, this should not be a very difficult problem.

Our weekly target thus becomes 3400 times 7 or about 24,000 mcg or 24 mg per week of lycopene.  The easiest way to achieve this goal obviously will be to eat two 1 cup equivalents of tomato soup each week.  Or combine 1 cup of tomato soup with some daily tomato juice plus a fairly liberal use tomato sauces that provide quite high lycopene from just a tablespoon of amount. The value for pizza is based on an average of some typical recipes, but keep  in mind that pizzas can be different, and some kinds may include no tomato paste.  Eating a half of a tomato based pizza can supply intake of half of the lycopene needed during a week.  An Italian study found a lower measured risk of cancer for those that ate the most pizza each week. A good finding is that our average US population probably eats the equivalent of about a half tomato equivalent per day of lycopene, so inadvertently has been achieving half of the potential benefit of this factor.  But few probably are obtaining the full healthful target, and many are obtaining little of this important and easy to achieve unique health benefit. 

Life Ahead now identifies amounts vs. goals and health benefits from lycopene intake from any entered diet using the above values.  The present food library includes these values for tomato juice, tomato soup, fresh and cooked tomatoes, catsup, and pizza.  Other foods such as spaghetti may or may not have included amounts of tomato sauces.  Lycopene values for such other foods are not included automatically, but users can add an estimated amount of tomato sauce included using the entry for tomato sauce. The program identifies cancer risk as modified by formula (2) above.  But if an intake of lycopene is changed at present age it assumes that the computed risk change will not fully develop until 15 years in the future because of the mechanism probably involved.  The risk change is computed in the year by year computation to develop gradually to this changed value at 15 years ahead, and then stay constant at the value for years beyond this. Even with this quite conservative approach the previously computed benefits for added lycopene intake can be substantial.

About Lycopene Supplements:  Lycopene supplements that include 5 or 10 mg or 5,000 or 10,000 mcg are available.  It will take only 2-3 per week of the 10,000 level pills or 5 of the 5,000 mcg ones to reach the target level of 24,000 mcg per week. Will these provide the needed benefit?   No verification of the value of these supplements was found here.  But it is unlikely that such verification will be achieved.  This is because it probably will take at least 10-15 years of lycopene intake to slow cancer sufficiently for any measurement from a clinical study to be useful.  This subject is discussed extensively in the other Life Ahead project analyses as for example that for Vitamin E and in the article on 'Concepts'.

Lycopene supplements have been shown to raise substantially the lycopene content in the blood.  And more than adequate research confirms that risk of cancer is related to blood levels of lycopene.  For nutrients such as omega-3 fats and folic acid that provide a near immediate response in risk level to intake it has been found the supplements provide benefits similar to that from their content in foods.  Thus it seems highly likely that lycopene supplements will provide the needed lycopene benefits if used over long time.  Thus the unusual health-interested person that finds all tomato foods distasteful or unacceptable can consider the alternative of taking supplements as a prudent action. But everyone else should try to get protection from the better established and enjoyable method of eating the actual tomato products needed.