Abstract: All but 3 of 54 observation study comparisons  found published confirmed that those taking vitamin E probably reduced their risk of cancer.  But an important qualification is that the vitamin probably slowed the progress of cancer on average by only about 1.4% or a compounded factor of 0.984 for each year of use.  Generally, it takes at least 20 years for cancer to develop, and a user should recognize that a benefit for this vitamin in reducing risk of cancer will require 10 years of use to obtain useful benefit.  The risk of each of 7 types of cancer appeared to be reduced by long term use of vitamin E.  Results of 16 primary clinical research comparisons of vitamin E and cancer for presumably healthy people were mixed as expected because theses studies did not have the resolving power to measure a useful effect during the short times of exposures used.

 

As will follow, clinical studies measure a quite different and much lower risk value for vitamin E than do observation studies.  Although the studies now done did not have the resolving power to meet the 95% statistical test, they usually developed risk values consistent with those expected for their duration and other conditions used. The actual individual results of 70 useful observation and clinical study comparisons of vitamin E and cancer are listed appended in Table E by type of cancer for convenient review and reference.  Overall this analysis of nearly all of the useful study results published affirms that the use of Vitamin E supplements over long time probably will reduce the risk of most causes of cancer by about 30%.  The average risk reduction for all observation studies was 29% and that for 12 case control studies of risk from amounts of Vitamin E in blood averaged 39%.

 

See other papers of antioxidants and CV disease for Vitamin E;  Vitamin A;  Vitamin C; and Selenium , papers of antioxidants and cancer for Vitamin A;  Vitamin C; and Selenium, and Antioxidants, Death from All Causes. Antioxidants, a Global Analysis, and Problems using Clinical Studies for Life Style Habits.

 

The Results of Actual Research:  Table E following provides the results of key observation and clinical studies published for the effect of Vitamin E on cancer organized for convenient view.  The observation comparisons found include results for the vitamin for all cancer and for cancer at individual sites including the breast, prostate, lung, colon, rectum, ovaries, cervix, bladder and oral and stomach.  All but 3 of these  54 studies suggested that Vitamin E reduced risks of cancer. 

 

Twelve of the opbjective study comparisons were studies relating amounts of Vitamin E in blood to the cancer risk of populations via case-control comparisions. These found an average risk ratios of 0.61 or reduction in risk of 39% for unidentified but probably long term exposures to the vitamin. 

 

 The 16 results from clinical studies of vitamin E and cancer were mixed and showed little net benefit.  Because the development of cancer requires a long induction period of at least 10 - 20 years, clinical studies done did not have the resolution power for identifying a useful risk for vitamins and cancer. But their results were generally consistent with what was found from observation study results  More on this will follow.                             

 

TABLE C
Cancer Type	Number of Comparisons	Average Risk Ratio
All Cancer	6	0.78
Breast Cancer	8	0.78
Prostate Cancer	13	0.70
Lung Cancer	7	0.69
Colorectal Cancer	9	0.64
Ovarian Cervical	3	0.53
Bladder Cancer	2	0.75
Stomach &Oral	2	0.88
All Cancer Sites	44	0.71

 Table C opposite summarizes reductions in risk for key types of cancer and for all 

 cancer for the taking of Vitamin E supplements. The risk ratio for the various cancer

 types appeared to average about a similar 0.70 or a reduction in risk of about 

 30%. These results were obtained mostly from use of supplements from 30 to 600

 IU per day, with a probable average value of about 150-200 IU per day.  As

 before, a qualification of these results is that the obtaining of these risk benefits 

 probably will require taking Vitamin E for periods of 20 or more years.

 

 Cancer Risks Depends on Duration or Exposure:  From Biochemical  

 Engineering and the analysis of cancer development it is likely that cancer develops 

 only slowly, with a risk compounding with duration of carcinogen use.  This behavior

 is found for cigarettes and cancer. The largest studies of cigarette smoking show that

 first events of lung cancer require more than twenty years of smoking.   Tests of

 carcinogens on mice show that this induction period for cancer can be longer than one half of their total life expectancy, and can be shortened with use of more potent carcinogens. This same behavior appears to occur for humans.

 

The benefit of antioxidants thus should accrue stepwise depending on the time during which this agent is present.  Limited by some useful direct information on the effect of antioxidant duration is provided in the available research.  A study of Jacobs (Cancer Epidemiol Biomarkers Prev 2001, 10:17) did find a substantial effect of duration of Vitamin C use on risk of colorectal cancer.  A study of  Giovannucci  (Ann Intern Med 1998, 129:517) found colon cancer risk to be markedly reduced after 15 years of use of multivitamins.  Perhaps the largest of studies, that for cancer prevention that enrolled nearly a million people, obtained 1289 bladder cases after 16 years of followup.  A noteworthy result found in this study may have been the benefit of Vitamin E.  A risk ratio of 0.60 or 40% reduction in risk was obtained for those that used Vitamin E supplements for more than 10 years.

 

A most interesting study by Pan (#O2 in Table E following), sugggests a clear relationship of risk and duration. Users of each of 6 antioxidants obtained benefits of about 4% per year of exposue, and obtained risk reductions afer 15 to 20 years of use.  The data supporting this follow: The large gap of a 25% different risk level between no use and only a half year of use is not explained.  It suggests those that started taking the nutrients had a somewhat higher risk at start than those that took no supplements.  But for measuring the  effect of duration it is best to use the minimal time of actual use as base. Starting with a 1.0 risk for less than one year of use, the average risk is reduced by a factor of about 0.96 or 4% per year.  This is similar to the reduction in risk for antioxidants on cardiovascular diseases. This unique set of risks show that the really important changes in risk become substantial only after 10 years of use. A remarkable results of this analysis was that the same behaviour occured for 6 different recognized antioxidants. The higher than average 0.80 risk for Vitamin C at 10+ years will change to a very productive risk of 0.59 when based on the starting or half year base.  Risk for vitamin E is only 0.44 at 10+ years use for a reduction risk of 56%. And as years of life continue, this risk could continue to decline at  factor about 0.96 per year

                                            Table D

Effect of Durations of Exposure and Risk of Ovarian Cancer
Antioxidant	No Use	<1.0 Yr	1 to 5 Years	6 to 9 years	10 Years or More
Average Yrs	0	0.5	3	7.5	15-20
Vitamin A	1.0	1.31	1.05	1.06	0.58
Beta Carotene	1.0	1.14	1.18	0.76	0.31
B complex vit	1.0	1.19	0.85	1.08	0.61
Vitamin E	1.0	1.11	1.08	1.15	0.49
Vitamin C	1.0	1.36	1.08	0.93	0.80
Selenium	1.0	1.41	1.24	0.91	0.55
Average Risk	1.0	1.25	1.08	0.98	0.56
Use 0,5 year as Base		1.00	0.86	0.78	0.45
Risk per Year of use		Base	0.95	0.97	0.95-0.96

  To gain more insight on this time of use and other factors producing 

  cancer a Global Analysis was done the of 44 available observation

  study results for vitamin E and cancer in Table E.  The studies of

  cancer development suggest that if a group of people had identifiable

  genetic risks and identifiable lifestyle all included individuals would

  develop cancer at the same future time of perhaps 20 or 30 years.

  But individuals of a population differ in genetics and lifestyle, and a  

  very few with high risks would suffer cancer earlier and others with

  low risks would suffer later or not at all.  Thus development of

  cancer in a population will develop gradually by some small amount

  each year.  We have to estimate our risk from results on such

  populations.

 

 The  Global Scientific Analysis of Vitamin E and Cancer:  This

  analysis was done using stepwise multiple regression trials on the 

  results of the 44 sets observation research in Table E.  Risk of cancer did not depend directly on amounts of vitamin E used but developed closer to the 0.5 to 0.333 power of amount used. The effect of amount measured in blood appeared closer to this type of relationship than it did to the direct amount of vitamin present.  The 0.333 power that might be true means that there may be only a modestly larger effect for say 400 IU than that of 100 IU in a supplement.  But a dose rate proportional to the 0.5 power of amount used was accepted to be conservative.   A possible effect of population average age was found, with older persons obtaining a larger reduction in risk for use of the vitamin. This may reflect mostly the fact many older persons probably have used vitamins for longer periods of time than did those younger.  No effect of user gender was found within the accuracy of the data available.

 

The effect of duration of use of vitamin E was explored from testing of various assumed durations.  For example groups of individuals at the start of an observation study having differing levels of vitamin E will have developed their respective risks from some prior time of exposure to similar amounts of the vitamin.  Their risks are followed for another 1 to 15 or more years in a prospective study.  The true time of exposure is that prior to the study start plus that in the follow-up.  A case control study takes a snapshot of risk for some past but unknown durations of vitamin use.  Increasingly best statistical fit of the results was obtained with longer assumed past durations of use of up to twenty years.  A clinical study measures only the direct duration that individuals took supplements and placebo and thus type of study usually will obtain a much lesser risk value than that measured in an observation study. Further, an observation study measures the full risk from lowest to highest risk of 5ths of a population.  The clinical study measures only the risk from the mean value of a population to a higher value included in a supplement. If those in the placebo group have been taking vitamin supplements or observed particularly good other habits as often been true, this higher amount of supplement vitamin being tested may produce no further advantage. More on the problems of obtaining valid measurements from clinical studies is included elsewhere on this site. 

 

This time-dependent effect developed from the global analysis and confirmed further above are supported even further by other interesting findings about antioxidants and cancer. Although it may take more than twenty years for cancer to develop from an average population, the time related effect suggests that it should develop sooner from an otherwise healthy  population having inherently higher than usual risks of cancer.  This has been confirmed by a multiplicity of findings.  For example, the importat research of Clark on Selenium (study CA1) started with a population that already had developed skin cancer. Clark found that risk of cancer on this population was reduced a highly significant 50%  in only 6 years.  The large Nurses study, B4 in Table E,  and some others found some significant and much larger than usual reductions in risks from various antioxidants supplements for groups have elevated family risks and for those having high alcohol consumption.

 

Smokers and those with Disease Probably may not benefit from use of Vitanin E or other Antioxidants. A number of studies have identified higher risk for smokers for use of antioxidants.  Best results appear in a study A3 appended of more than a million men and women for a time of 14 years.  The risk was developed for use of any vitamin supplement or use of individual A, C or E vitamin. The risk for non-smokers was 0.86.  The risk of current smokers for use of the vitamins was 1.06 or an increased risk..  This is more than a 20% difference of quite high significance.  The limits for no smokers were 0.74-0.99.  The limits of smokers were 1.06 to 1.26.  This suggests  that smokers probably should not take vitamins or vitamin supplements.

 

A similar results appears likely for survivors of a disease.  This same very large study showed risks of 0.87 for healthy men and 0.90 for women for all types of cancer from use of any antioxidant.   This included risks for both non-smokers and those of smokers.  But men and women that had been diagnosed with cancer had further risk of death from this cancer of 1.18 and 0.99 respectively. This finding from an important objective type study explains the failure of clinical studies to find benefits for persons with prior disease.  Antioxidants do not appear to be useful for protecting those that already contracted a disease.  First the processes that lead to death from disease override any contribution of antioxidants. Second, those having disease will be taking other medicines that could provide the benefits conveyed by antioxidants.

 

The Formula for Vitamin A and Cancer:  This model provides a rough picture of how the various usage of vitamin E most probably would reduce risk. The actual formula is appended to Table E following.  A best fit for the effect of duration of exposure was obtained at a reduction in risk of 1.4% per year of taking the vitamin.  The is a compounding benefit of 0.984 change in risk for each year the vitamin was used. This is a smaller benefit than the 2 to 4% per year or 0.96 to 0.98 change in risk for use of vitamin E reducing risk of heart disease.  I have noted in Table E the estimated change in risk per year of exposure for the various studies that was observed. 

 

Some values from this formula for observation studies follow.  The numbers in bold identify a starting average level of risks found for conditions in the observations studies. The different numbers for each risk show how changing just this value might change risk of obtaining cancer.

 

A Formula for Risk of Cancer from use of Vitamin E:.

 

             Risk Ratio of Vitamin E, Cancer =  Exp ( -0.00116 *  yrs of exposure * Vitamin E in IU^0.50) 

 

Table D shows risk from the formula:                               

 

Table D          RISK RATIO for EFFECT of VITAMIN E on RISK of CANCER
Duration of Use in Years	1	5	10	20
Vitamin E in IU
30	0.994	0.97	0.94	0.88
100	0.988	0.94	0.89	0.79
200	0.984	0.92	0.85	0.72
400+	0.977	0.89	0.79	0.63

                                                                                   

Note that values of risk for only 5 years develop to only 0.89 or 11% even for maximum use of Vitamin E.  Practical clinical studies on humans usually cannot measure a risk that is this small, and study authors usually claim  "No effect found"  This causes constant statistical confusion because a more likely conclusion may have been  "No effect was fund within accuracy limits of the study. These risk differences may be somewhat higher and somewhat lower at high and lower individual age.  Note that these values show a lower and more conservaative valuation of duration of use than did the previously discussed actual results for ovarian cancer

 

Results from Clinical Studies of Vitamin E:   There is a widespread assumption by researchers today that a clinical study provides a more accurate measure of an agent than does an observation study.  This assumption is true for the study of a medicine or drug that is a new agent to users and that is expected to produce a result within short time. But this assumption is not true for the measurement of a lifestyle factor that develops benefit over long time.  The idea that a clinical study is best also is not true for valuing the benefit of using more of an agent such as an antioxidant that already is present in the diets of most the users.

 

A clinical study measures a quite different value than that developed from either a case control or prospective observation study.   I show results of the 3 major clinical studies that measured the risk of Vitamin E, and how these results compare with an estimate of risk from developed from observation studies using the factors that follow and that are in an  appended formul.

 

Study         Location              Duration   Amt of Vitamin E   Risk Value      Limits            Expected Value with              

                                              in years        Vitamin E             Found                               zero risk of placebo                              

CL!         China, Blot                 5.5            290 equiv             0.87         0.75-1.00               0.91

CL2        US, Lee                     10               300                     1.01         0.94-1.08               0.90 - 0.95                                             

CL3        Finland, Coulter          6.1              75                      0.91         0.74-1.12               0.94

 

Studies CL1 and CL3 produced results consistent with those predicted from observation studies well within their margin of error. But this comparison reveals that these expensive clinical trials had little chance of success in finding a statistically useful result for vitamin E. .  The average of all 15 results of clinical trials of different forms of cancer listed in Table VE show an average risk factor of about 0.95 that would be similar to that forecast for the conditions involved..  The CL1 study included multiple antioxidants.  I show an approximate equivalent for this as Vitamin E.

 

There are problems with study CL2.  First, compliance here (and in other clinical studies)  was only about 75% in the vitamin user group. Second, 39% of all users were taking vitamin supplements that probably would have contributed most of the benefit obtained by the supplement user group.  Third, this was a much healthier that usual group of women that had a lower incidence of disease than average. Adjustment for these factors would raise the expected value to above 0.95 that is within the error margin of the study.  In summary, the results from clinical trials appear reasonably consistent with results obtained in observation studies after reconizing the inherent differences in what they actually  measured.  But the clinical studies did not have the resolution power to endorse any conclusion about vitamin benefit.

 

A General Fotmula for Vitamin  E and Cancer:  It is interesting to compare the average actual risk values found in observation studies of 0.70 in Table C with a  Global Formula values found for cancer risk from Vitamin E in Table E.  This suggests that the actual average durations of diets valued probably averaged about 20 years.for a average use of Vitamin E of about 200 IU per day.  These conditions would develop the average value for risk shown for the Global Formula.  The actual duration of observation studies averaged about 10 years.  This means that the individuals entering studies had developed use of and benefit the nutrients measured for a period of about 10 years prior to starting the studies.  A usual case control study or diet valuation of Vitamin E identified a 20 year average use of the nutrients. 

 

A Global Formula for predicting the risk for any type of study, Blood, Case Control, Prospective, or Clinical follows Table E. . This shows how the different study methods will develop risks for Vitamin E in reducing risk of most kinds of cancer.   It confirms that this research is consistent in showing a highly probably if modest reduction in cancer risk from long time use of Vitamin E.  It explains why results of clinical studies differ from those of prospective studies.

 

It remains possible that some people for some combination of habits will not obtain reduced risk of cancer from Vitamin E.  This could be due to the simple fact that their induction period for developing cancer is longer than usual.. The large study of  US nurses, B4 in the Table E , found no or very little effect of Vitamin in reducing  risk of breast cancer. This study valued a much healthier group than average, and many were taking other antioxidants.  The vast majority of people researched to date, however, did find a useful health benefit from the taking of this vitamin. And comprehensive reviews of all key research on vitamin E shows thant it also reduces risk of heart disease, macular degeneration, dementia, and all causes of death. 

 

Vitamin E in Foods:  No research information considered useful regarding a benefit of Vitamin E in foods in reducing risk of cancer was found. An average amount of Vitamin E in foods is about 9 IU per day, with variation among populations of perhaps 6 to 12 IU/day. This difference of only 6 IU is too small an amount to produce a credible benefit measurable via today's population research study method. As per Table E, multiple research studies are needed to verify a benefit even for a Vitamin E difference of 200 IU per day. See more about the problems of Vitamin E in foods in the discussion of Vitamin E and heart disease. 

 

How Life Ahead Computes Risks of Vitamin E:  Life Ahead does not compute a direct effect of Vitamin E on risk of cancer.  Rather, it develops an estimated total antioxidant value from amounts of Vitamins A, C, E and Selenium in both foods and supplements, and imposes a limit on the total of all antioxidants that can be effective. This is the same method as that used for antioxidants and cardiovascular diseases.  For further conservatism Life Ahead uses a maximum benefit as that from 20 years use of antioxidants. Vitamin E is recognized as the most potent of these antioxidants in this valuation.  The use of 200 IU per day of Vitamin E alone produces an antioxidant level not far from the maximum now accepted from any amount of use of these four antioxidants.  But a health-interested person should insure useful intake from each of these antioxidants as they may have complementary benefits.

 

See the accompanying discussion of Vitamin E and heart disease for Types of Vitamin E and of the overall potential benefits of Vitamin E in extending Well-Days of life.  See the Antioxidant Global Analysis  for more on how Vitamin E and other antioxidants participate together in producing benefit.

 

Understanding the Research in Table E Following:  This table provide most of the important useful research in on risks found published to latest date listed.  Most researchers and health writers base their ideas on just a few most recent studies because it can take weeks or months of time to produce this type of a more complete review.  But these comprehensive listings are an essential need to obtain a most up-to-date and correct answer to a most likely risk.  The important finding of research is the risk ratio, or the risk of disease of those with a better health factor vs. those with a base or usually average or poorest health factor.  A risk ratio of 0.5 means risk of those with better health factor have half the risk of those with the poorer one.  A ratio of 0.25 means they have only 1/4th the risk; a ratio above 1.0 means a negative result from the factor.  Unless mentioned otherwise, all risks shown in Life Ahead tables use this ratio method, and research results presented differently by researchers are correspondingly adjusted.

 

Most risk ratios are followed by an error margin, as limits of 5% to 95% probability.  If a ratio is 0.75, and the limits are 0.5 to 0.9, the study really produces a likely result of a risk lying somewhere between 0.5 and 0.9. The usually quoted risk simply of 0.75 is quite inaccurate. But because the upper limit is still below the null value of 1.00 this result usually will qualify in the study publicity as "Statistically Significant"  If the error margin is say 0.4 to 1.15, and the upper level is above 1.00, the individual study usually will be "Not significant."  Researchers often say incorrectly that "We found no effect" when a result really is "Not 95% significant"   The produces Statistical Confusion that can be very misleading. 

 

Because most health studies have such high error margins, it is necessary to have results of multiple studies to obtain a probable truth.  Two studies, each finding a risk of 0.75, and each with say error margins individually of 0.45 to 1.10 can define in combination a quite significant result even though each individually did not include sufficient data and was "Not significant"   A best answer thus is revealed by what ALL of the RESEARCH shows in combination.  This is what the tables following attempt to show.

 

Look down at the risk ratios found.  If risks from most or all studies show values lower than 1.0 you can be assured that the effect being measured is both real and of high significance. The fact that some individual studies do not reach 95% significance individually can be meaningless when viewing multiple results.  About a third of all health research studies do not have the resolving power to produced a result of statistical significance.   5-95% limits that each are below 1.00 at usually confirm an individual study as significant in its own right.  If most studies have risks well below 1.00 and error limits also below 1.0, the truth may be established at levels of millions to one.  Some studies include 3, 4 or 5 results at differing "dose" or amounts of factor levels.  If these show steadily declining ratios with dose, significance becomes even larger.  Some studies show "p" ratios of significance.  A p value of 0.05 or denotes 95% probability.  A lower p value of 0.01 is 99% and a p of 0.001 can define significance at a thousand to one.