Dr. Len's Cancer Blog

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Dr. Len's Cancer Blog

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Clinical Trials: Patients' Right to Know Results

by Dr. Len April 26, 2006

It has been a quiet week on the cancer news front, which gives me an opportunity to discuss a question that has been on my mind since I first read an opinion piece in our journal Cancer recently.

 

The question is simple: Do patients and their families have the right to know the outcomes of clinical trials in which they participate?

 

According to a highly regarded cancer researcher, the answer is not so simple, and is essentially “no.”

 

I don’t agree.

 

Actually, to be honest, it is a position that has never crossed my mind.  My assumption has always been that, for most clinical trials, if you agree to participate you should know the results.  Short, simple and to the point.

 

There are different types of clinical trials underway in cancer treatment.  Some are prevention trials with fairly safe, well known drugs (although the recent Vioxx situation has many folks wondering how safe is safe).  Other trials are treatment trials, perhaps where two known accepted treatment regimens are compared to each other.  Other trials may compare a new drug or treatment program to an accepted, standard therapy.  The most difficult trials may be those where a drug is used for the first time on human subjects.

 

No matter the type of trial, I would assume that the patient and their families might want to have the opportunity to learn the results of the trial.  After all, they put their bodies at risk, so to speak, so why shouldn’t they find out if there was a benefit?

 

That may be time consuming for the investigators and their staffs, and it may be difficult to explain some of the intricacies of trial results in simple terms that most lay people can understand.  But at least, to me, it would seem to be the right thing to do.

 

The author of the article does not agree.  He writes, “It is reasonable to conclude that researchers currently do not consider this activity a required component of their obligations to participants in clinical trials.  Rather, the major focus of investigators is on insuring the autonomy, and protecting the safety, of research participants both immediately preceding and during the trial and not on an ethical obligation to subsequently inform individuals about what researchers have learned that may be of benefit to future patients.”

 

In other words, if you read it in the newspaper or see the news on television you got your answer.  And, if it doesn’t make the news, that’s the way it is.

 

The basis of this position appears to be that knowing the results doesn’t really make a difference to the individual, since the treatment has already been provided.  Only if knowledge of the results could influence the care of the patient should they be advised of those results (for example, the women on tamoxifen as part of the recent STAR trial should be told that raloxifene had fewer side effects, and should be informed so they can consider whether or not they want to discontinue tamoxifen as a prevention strategy for breast cancer for post-menopausal women at high risk).

 

Another argument put forth in the paper is that patients and families could not understand the nuances of interpreting the design and results of the trial. 

 

Here, I would compare this statement to the efforts made by many excellent health media journalists who do their best to grasp the key points of a study and provide information to their reading, viewing or listening public.

 

If they can do it, why can’t the investigators?

 

Sometimes intelligent folks such as doctors and cancer researchers think in details that most of the public are simply not interested in.  They get buried in weeds about their work that don’t transmit well to public audiences.

 

If they can boil things down for 10 minute or one hour news conferences, my bet is they could boil down the results of their studies for the patients who committed themselves to advancing the particular research endeavor.

 

Another comment in the paper had to do with the risk of causing harm to the patient. 

 

For example, the patient received treatment B, and the study showed that treatment A was better.  But the patient is alive and well.  Can the patient deal with the fact they received B instead of A, although for that individual B worked fine?  Or what would happen if the patient didn’t do well?  Would they or their family have severe misgivings that the patient hadn’t had the “successful” treatment?

 

If we knew the answer to the question before the study started there would be no reason to do the study, not to mention the fact it would be ethically unjustifiable. 

 

We do clinical trials to answer questions to which we do not know the answers.  That is something that the researchers have to explain to their patients when they go through the informed consent process.

 

Furthermore, studies are supposed to be monitored very carefully so that if it becomes evident that one treatment is clearly superior to the other, the study can be halted and all of the participants can get the benefit of the superior treatment.

 

We cannot forget that not every trial shows an improvement with a new treatment over an old one.  Sometimes, the new treatment is not superior, and sometimes it is actually demonstrably worse than the existing standard treatment.

 

The author does offer a compromise solution that addresses the questions raised in the article. 

 

He writes, “One solution may be to consider adding a section to each IRB (institutional review board) approved consent form that specifically discusses the possible reasons why a patient may elect to receive or not receive the results of a research study in which they have participated.  A major advantage of presenting this discussion at the time of trial entry would the conflicting ethical arguments can be highlighted in general terms, without any knowledge of the actual study outcome.”

 

That is a reasonable suggestion, and at least puts the question on the table so there are no misunderstandings at a later date.  It also empowers the patients and their families to make a selection and offer guidance on how much information they would like.  Some folks aren’t interested or don’t want to know; others want to know everything.  At least this approach provides an option and an opportunity.

 

We do not do a good job in this country of getting folks into clinical trials.  Clinical trials are the primary and necessary mechanism available to us which helps us advance the science of cancer treatment.

 

We need to have a better understanding of what would improve participation in clinical trials, beyond the issues of costs and whether they are covered by insurance, or how far the patient lives from a clinical trial location.

 

We need to understand what motivates patients and families to participate in trials, and we need to know how much they view this participation as good for themselves and good for society.  We need to know what they want to know.

 

And if they want to know the results of the trial, or if their families eventually want to know, it is my opinion that we should make every effort to comply with that request.

 

Filed Under:

Cancer Care | Research | Treatment

A New Era for Breast Cancer Prevention?

by Dr. Len April 17, 2006

This has turned out to be a more interesting day than initially planned.

 

We received notification late Friday afternoon that the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project were going to release the results of their Study of Tamoxifen and Raloxifene (STAR) trial that had started in July 1999 and included almost 20,000 women.

 

The results were released at a news conference at 2PM this afternoon.  According to the presenters at the press event, raloxifene was the superior medication to prevent breast cancer in women at high risk.  I was quoted by one reporter as suggesting that I did not agree completely with that assessment.

 

The trial was designed to answer the question whether raloxifene (commonly known as Evista, which is in wide use for the treatment of osteoporosis in post-menopausal women) was as effective as an older drug called tamoxifen in reducing the risk of developing breast cancer in post-menopausal women at high risk.

 

Tamoxifen and raloxifene are both drugs which belong to a class of medicines called SERMS.  These drugs have both estrogen and anti-estrogen like effects in the body.

 

While raloxifene is effective in reducing the risks of fracture in post-menopausal women, tamoxifen has long been used as a treatment for recurrent breast cancer and for the adjuvant therapy of women (both pre- and post-menopausal) with breast cancer.

 

A number of years ago, tamoxifen was also demonstrated to reduce the risk of breast cancer for women at high risk, as defined by a number of factors such as age at onset of their periods, the date of their menopause, age at first pregnancy, and family history among others.  The amount of the benefit was close to 50% reduction in risk. (Read "Factors Associated with Decreased Risk of Breast Cancer" in this link.)

 

It was approved by the FDA to be prescribed as a risk reduction medication in 1998.

 

Tamoxifen as a risk-prevention strategy for breast cancer never really took off.  No one is absolutely certain why, but it probably had to do with several factors, such as:

 

·        Whether a woman and/or her doctor were aware that she was at high risk and tamoxifen would be effective;

 

·        The side effects of tamoxifen, which included an increased risk of uterine cancer (in women who had not had a hysterectomy), increased risk of blood clots in the legs as well as blood clots that traveled to the lungs (pulmonary emboli) and cataracts, among others.

 

A colleague of mine once referred to the accentuation of these risks as the “demonization” of tamoxifen.  Nonetheless, the risks were real and because we are talking about prevention in women who may have otherwise been completely healthy, the drug never got traction in the general medical and lay communities for a very valid indication.

 

Raloxifene, on the other hand, was a drug in fairly common use for the prevention of fractures related to osteoporosis.  It was prescribed regularly by primary care doctors and gynecologists for their patients.  There were some known side effects, including an increased risk of blood clots.  But there was no indication that it shared some of the other more serious side effects of tamoxifen.

 

But it was other information that lit the fire under raloxifene as an alternative to tamoxifen as a breast cancer prevention drug.  There were some trials that found, as a secondary observation, that raloxifene appeared to share the benefit of tamoxifen in reducing the risk of breast cancer. (See prior link above about decreasing risk of breast cancer.)

 

So now we have the results of the head-to-head comparison of the two drugs as announced this afternoon and is being widely reported as I write this.

 

Basically, raloxifene and tamoxifen were equally effective in reducing the incidence of invasive breast cancer in women at high risk of developing the disease.

 

However, tamoxifen was more effective than raloxifene in preventing non-invasive breast cancers commonly called DCIS (ductal carcinoma in situ) and LCIS (lobular carcinoma in situ).

 

These findings were consistent with past research.  In fact, in prior studies, there was no evidence that raloxifene reduced the incidence of either DCIS or LCIS.

 

(For your information, the American Cancer Society estimates that 212,920 women in the United States will develop invasive breast cancer in 2006, and 40,970 women will die from the disease.  61,980 women will develop non-invasive forms of breast cancer.)

 

In looking at toxicity, raloxifene had fewer side effects than tamoxifen.  There were fewer cases of uterine cancer in the raloxifene-treated women who had not had a hysterectomy compared to the women treated with tamoxifen. There were also fewer blood clots and pulmonary emboli in the raloxifene arm of the study.  There were fewer cataracts with raloxifene.

 

There were some similarities as well.  Both drugs were equally effective in preventing bone fractures.  Quality of life was similar (although the investigators stated in their news conference that menopausal symptoms and vaginal complaints were more numerous in the tamoxifen treated group).  The numbers of strokes were similar in both groups.

 

The only side effect that the investigators said was statistically significant, however, was the cataract difference.  The others, although apparently very close to significance, could still have technically been due to chance—which means there may not be a difference at all (although most physicians would agree that if you get close to significance, it may be nitpicking to say that the effect isn’t a real one).

 

So here is my dilemma: the news release for the trial pointed out that tamoxifen reduced non-invasive cancers, while raloxifene did not.  Is this difference significant enough to give women and their doctors pause in selecting one drug over the other?  Or is the reduction in severe side effects, understanding that the non-invasive cancers can be effectively treated, the more important element to consider as a woman makes her decision?

 

The news release quoted the well respected president of the American Society of Clinical Oncology, Sandra Horning MD, as saying, “We look forward to further discussion and analysis at the ASCO annual meeting that will address the observed differences in toxicity and prevention of non-invasive breast cancers with the two treatment approaches.”

 

My conclusion was that, although raloxifene would be a good choice for many women, we can’t ignore the fact that tamoxifen is better at reducing the non-invasive cancers.

 

Non-invasive cancers in the breast are, fortunately, usually eminently treatable.  They are not “incidental” for the women who are diagnosed with them.  They involve emotions, treatment, expense, and concern over the future.

 

Treatment may vary, depending on the decisions made by the women involved and their physicians.  Usually, it involves a lumpectomy with radiation therapy and adjuvant therapy with tamoxifen.   Some women may opt for mastectomy.

 

So, even though these are usually considered “benign” cancers, they do carry with them a diagnosis that has meaning to women and their families.  And, they also mean that the woman is at significant risk of developing a second, invasive breast cancer in the future.

 

How much of an issue this is remains unclear to me as I write this.  I actually believe strongly that discussion by medical experts will help guide us where we should be going with information such as this, and what recommendations we should be making to our patients.

 

For women who have the option of taking a medication to prevent breast cancer, there are now two choices.  Currently, only one is approved by the FDA but most of us anticipate that the company that manufactures raloxifene will send a new indication request to the FDA in the not too distant future.

 

This is really the essence of informed decision making.  If a woman will not take tamoxifen to prevent breast cancer because of her concern regarding the real risks of tamoxifen, then raloxifene represents a significant option.  There are probably many women who have been offered tamoxifen for just this purpose, and have declined to take it because of the risks.  After all, many of these women are in good health, so any detrimental effects are very real to them.

 

But I suspect that there is going to be continuing discussion among the experts as to what the next step should be for women who either are less concerned about the side effects, or who have had a hysterectomy and are not at risk for uterine cancers, and whose doctors would like to offer some reduction in the risk of non-invasive cancers as well as invasive cancers.

 

Let me be very clear:  This study is an important one, done by highly reputable organizations and investigators, and represents a major advance in the prevention of breast cancer for women at high risk.

 

But the presentation today, important as it is, is only the beginning of the road for this discussion.  And I, for one, eagerly await the opinions of my expert colleagues on their interpretation of this exciting report.

 

Estrogen and Breast Cancer: Not What We Expected

by Dr. Len April 11, 2006
You can't always get what you want
But if you try sometimes you just might find
You get what you need
 
                                                --Rolling Stones
 

For years, we have had many studies that implicated hormone replacement therapy (HRT) with estrogens in increasing the risk of breast cancer in post-menopausal women who took them for relief of menopausal symptoms and other medical problems facing older women.
 
The Women’s Health Initiative, which has been the topic of several of my blogs including one I have posted recently, put to rest many of the myths about the medical values of HRT. 
 
The initial report of the portion of the study that treated some women with combination therapy with the hormones estrogen and progestin clearly showed an increased risk of breast cancer.  It also demonstrated increased difficulty in detecting those cancers at an early stage due to increased breast density which interfered with the interpretation of mammograms.
 
At the same time, there was a parallel study underway which was evaluating the use of estrogen treatment alone for women who had a prior hysterectomy (combination therapy is used in women who still have their uterus in place, since the progestin has been shown to decrease the risk of uterine cancer which occurs when estrogen alone is given to women with an intact uterus.  If the uterus has been removed, then there is no need to give the progestin).
 
In this second study, reported initially in 2004 in the Journal of the American Medical Association, there was once again evidence of toxic side effects from the estrogens.  The study found an increased risk of stroke, without any benefit in reducing the risk of heart disease.  As a result, the study had to be stopped early to avoid any further harm to the women who were participating.
 
But the investigators noted that there did not appear to be an increased risk of breast cancer in the women who took only estrogens compared to those who took placebos.  And, in fact, for some women the risk of breast cancer may have actually been decreased.
 
There has been substantial criticism of the WHI study for a number of reasons.  The practical problem has been that, for many women, hormonal replacement therapy is critical for their general sense of well-being.  Doctors and patients alike are confronted with the dilemma of prescribing and/or taking a medication that may be helpful, but has many serious and undesirable side effects.
 
Over the past couple of years, some researchers have begun reexamining the data, and doctors and patients alike now understand that hormonal therapy should be used at the lowest dose for the shortest time to control menopausal symptoms, and that women need to understand the risks and benefits of the treatment.
 
 
The short, the general answer is: no.  And that was a surprise.
 
The study, in brief, recruited almost 11,000 women from ages 50 to 79 who had a prior hysterectomy.  One half of the women were assigned to treatment with low dose estrogens, and the other half were given a dummy pill, or placebo.
 
The women were followed carefully, including scheduled physical exams and mammography.  On February 29, 2004 the participants were instructed to stop taking their medications because of the increased stroke risk noted above.  292 women had developed some form of breast cancer by that time.
 
What was interesting to me was that slightly over half of the women in both groups (including those on the placebo) had stopped their medications for the most part because of perceived or actual side effects caused by the medication (that means that almost 1 out of 5 women taking the dummy pill thought they had side effects from the estrogen, which in fact they were not taking; some of these women may have also had an unsatisfactory response to the placebo, which might have explained the reason they stopped it).
 
When the entire group of women treated with estrogens and placebos was evaluated, there was no increased risk of breast cancer in the group treated with estrogens compared to the group that received a placebo.  There was actually a slight decrease in the number of cancers in the women taking estrogen, and when examined further, most of this decrease was in women with early stage cancers.
 
Ductal carcinoma in situ (DCIS), a non-invasive and very early form of breast cancer, was also decreased in the women taking estrogen, but lobular carcinoma in situ (LCIS), another less common form of early breast cancer, was not.  The implication here is that estrogens may decrease the risk of DCIS which is hormone sensitive, compared to LCIS which is not hormone sensitive.
 
Then there is the confounding fact noted above that over half of the women who were assigned to estrogen HRT stopped taking their drugs sometime during the study period.
 
When we normally evaluate research trials, we do it on a basis of what is called “intent to treat analysis.”  What this means is that once you are assigned to a treatment group, you are considered part of that treatment group, even if you don’t get the treatment or withdraw from the treatment program at any time.
 
When the investigators took a look at women who actually took the estrogen treatment for the entire time of the study, and included data for women who stopped taking their estrogen up to six months after they discontinued the medication, they found something very interesting.  The estrogen actually reduced the risk of getting breast cancer by 33%!
 
This is the finding that was not expected, and was very surprising.
 
The investigators also found that in some groups of women, namely those with a lower risk score for getting breast cancer, those with no first-degree relative (mother, daughter, sister) with breast cancer, and those who have no history of benign breast disease, there also appeared to be a protective effect with estrogens.
 
In the post-menopausal women who had no prior hormone use, estrogen alone appeared to decrease their risk of getting breast cancer.  This was not the case if the women had previously used hormone therapy prior to entering the study.
 
Finally, one interesting side note to this study is that the investigators found no evidence that hormone therapy increased the risk of breast cancer more for thinner women than overweight or obese women, in contrast to the report I wrote yesterday.
 
Given the fact this is a randomized controlled trial, which is generally considered the highest quality of medical evidence, it appears that the use of estrogens alone in post-menopausal women who have had a hysterectomy not only does not increase the risk of breast cancer, but it may actually decrease the risk in certain circumstances.
 
There is a price to be paid, however, and that is the increased risk of stroke which was reported previously from this study.  And, women who took estrogen had an increase of “call backs” for short-term repeat mammograms because of suspicious findings compared to women who were taking the placebo pills.  There was also an increase in the number of breast biopsies in the treated women beginning after 2 years of estrogen HRT.
 
How does all this fit together with what we currently know about hormonal influences on breast cancer development, prevention and treatment?
 
I can still recall a discussion with one of my medical school professors around 1970 (he was a surgical oncologist at the University of Pennsylvania) regarding estrogens and breast cancer.
 
At that time, we faced many of the same questions being asked today regarding the role of estrogens and breast cancer.  We didn’t have tamoxifen at that time, and high dose estrogen therapy was a common form of endocrine therapy that we used to treat women with recurrent disease.
 
And it worked.  For some women it worked well for many years.  And, when we would stop the therapy because the cancer was progressing, we would occasionally observe the cancer would regress as well.  By the same token, if we removed the ovaries of a young woman with metastatic disease, the cancer would regress.  Different approaches in different circumstances, and both frequently brought positive results.
 
The essence of the professor’s comment was that it was the changes in the hormonal environment that explained the role of estrogen with regard to breast cancer.  Change the environment by adding or removing estrogen (in those days, by doing an oophorectomy in pre-menopausal or peri-menopausal women), and you can benefit women with breast cancer.
 
Low and behold, in 2006 after many years of study in a detailed randomized trial, the investigators in this study came to the same conclusion.  It is the change in the hormonal environment that explains the benefits of various drugs in preventing recurrent breast cancer, or treating recurrence when it happens.  And, as demonstrated by this study, increase the amount of estrogen with medications, and the risk can be reduced.
 
As the authors note, “These data are consistent with breast cancer cells being susceptible to estrogen fluctuations either above or below that tolerated by normal breast glandular tissues.”
 
My professor may have been way ahead of his time.  Over the years, a substantial amount of expert medical opinion was generated that suggested estrogens were plain bad for women because they increased their risk of breast cancer.  Now, the experts are saying change the level in the blood, up or down, and you decrease the risk.
 
We must never forget that these medications may increase the risk of stroke.  But for many women who have had a hysterectomy and who suffer from severe menopausal symptoms, they may now have one less concern to worry about if they make the informed decision to initiate short term hormonal therapy with estrogens.
 
Which brings me back to the Rolling Stones: It has taken a study of this size and this duration to prove that you don’t always find what you want, but you may get what you need.
 
Now, maybe there is some satisfaction for those who have questioned the estrogen/breast cancer hypothesis, and comfort for women who may benefit from this medication.
 

Hormone Therapy, Race, and Breast Cancer Risk

by Dr. Len April 10, 2006

One of the serious problems we have to confront in medical research is the fact that much medical research and investigation has been focused predominantly on white men. 

 

Over the past several years, as recognition of this problem has increased, more attention has been paid to including women and people of color in various clinical research programs.

 

The implications are significant, because we are now have less confidence that something discovered to work in white males or white men and women applies to other ethnic groups the same way.

 

One recent study that has received wide attention and has had significant impact is the Women’s Health Initiative (WHI).   This study, which reported several years ago on the significant medical risks of hormone replacement therapy in women, resulted in a significant decrease in the use of hormone pills in post-menopausal women. 

 

One key observation from the WHI study was that women who took combination hormone replacement therapy with estrogen and progestin had a higher incidence of breast cancer, especially if they had taken it recently over a long duration.  Subsequent reports indicated that in women who had a prior hysterectomy and only took estrogen as their hormone replacement did not have an increase in the risk of breast cancer.

 

But most of the women participating in that study were white and only about 10% were women of color.

 

Since breast cancer occurs less frequently in black women, but has a worse outcome, can we assume that the effects of hormones are the same in black women?

 

A study reported today in the Archives of Internal Medicine asks that question, and provides some insight that is interesting but may not be definitive.

 

The article in question reports the results of a several year study called the Black Women’s Health Study. The study began in 1995 with the intention of following a large number of black women aged 21-69 over the years with questionnaires to determine their health status.  64,500 women participated in this research program.

 

Among the questions asked were those related to the use of hormone replacement therapy, menopausal status, and the development of breast cancer.

 

23,304 women were age 40 or over either at the start of the program, or turned 40 during the years 1995-2003 and were analyzed as part of this report.

 

The authors reported that 615 women developed breast cancer during the study.  Of these, 364 never used hormones; 40 had used hormones in the past; and 210 used hormones recently.  Of the recent users, the majority (134) used estrogen alone, while 67 used combination therapy.

 

The bottom line, according to the information presented in the article, was that long term use of hormone replacement therapy increased the risk of breast cancer by 58% in women who had used hormone therapy for more than 10 years, compared to those who had never used hormones. 

 

Estrogen alone increased the risk of developing breast cancer by 41% in women who used the medication for 10 years or more.  Combination therapy with estrogen and progesterone increased the risk of developing breast cancer by 45% in women who used the medicines for 5 years or more.

 

Perhaps most interesting was the observation that among women using hormone replacements, the drugs had a greater impact on the risk of developing breast cancer in  thinner women using hormone replacements than on more obese women who used the drugs.

 

At first glance, this study would appear to say that if you use hormone replacement therapy, and you are black, you have an increased risk of developing breast cancer no matter which type of hormone therapy you used, so long as the use was recent, and 5 or 10 years more in duration.

 

But that is not consistent with the larger WHI trial noted above.  In that study, the increased risk of getting breast cancer if you used the combination of hormones was 26% after 5 years, and, if you took only estrogens (these women all had hysterectomies) your risk of breast cancer was actually decreased.

 

What we have here is different information from two studies in two basically different ethnic populations.  So what explains the differences?  Is it due to racial differences, or some other factor?

 

The answer, in my opinion, is that the two studies are not comparable and the study reported above may not be the final answer to this question.

 

First, the studies are fundamentally constructed differently.  The Black Women’s Health Study collected information over several years, but did not assign women to groups where one group took hormone treatments and the others did not.  The WHI on the other hand was a randomized controlled trial, and although I have had questions regarding some aspects of the program, I cannot fault the fundamental study design and benefits of a randomized clinical trial.  This research approach is always more preferable to an observational study, even one that collects data in a forward-looking manner.

 

But there is a more fundamental question for me in reviewing the currently reported study, and that is in what we call “statistical significance.”

 

It is difficult to explain “statistical significance,” so bear with me as I try.

 

In simplest terms, when you compare data from one group to data from another group you measure what is called “statistical significance.”  That is a measure of how “solid” the differences are between the two groups, and whether or not there is a possibility that the difference may be due to chance.

 

If the groups are large, and the differences substantial, then the “statistical significance” is going to indicate that the differences are real.  But if the numbers are small, and the differences close to each other, then the statistics will show that there is a possibility that the differences could be due to chance alone, and cannot be relied on with a great deal of confidence.

 

In the Black Women’s Health Study, the number of women in each of the two groups who developed breast cancer (those who took hormone replacements and those who did not) are small. 

 

In addition, the increased risk ratios are not large for the most part, and when you examine what we call the “confidence intervals” we see they vary widely.  That means the numbers for the most part do not have a great deal of statistical difference (or separation), which would allow me to place great confidence in their findings. 

 

In other words, there is too great a possibility that the numbers are due to chance alone.

 

Because of that, unfortunately, I cannot necessarily agree with the authors that their findings prove the point that any hormone therapy will necessarily increase the risk of breast cancer in black women.

 

That does NOT mean that it is safe to conclude the alternative, namely that all hormone therapy is safe for black women.  It is simply that this particular study at this particular time doesn’t allow me to draw the conclusion that there are differences in risks of hormone therapies between black and white women.

 

I would anticipate that if this study continues for many years, the quality of the data will improve considerably.  The vast majority of the women in this study were in their 40’s, which is not the primary age when women develop breast cancer.  Follow these women for another 20 years, and the data may indeed become more informative.

 

As to the question of whether leaner women (defined as a BMI less than 25) who used hormones had a greater risk of developing breast cancer than more obese women, the data in that case are a bit stronger, particularly for women who used estrogen for more than 10 years.

 

Why that is the case is uncertain.  We do know that in post-menopausal women there is a greater risk of breast cancer in obese women than women of normal weight.  This is thought due to the fact that fat cells increase the amount of estrogen circulating in the blood.

 

Why additional estrogen in hormone pills would increase breast cancer risk only in lean women is uncertain, and is deserving of further study.

 

So, bottom line, we still do not have an answer as to whether black women who use hormone medications differ in the risk of developing breast cancer compared to white women who use hormone replacement therapy.

 

Hopefully, the authors will continue their study and update their results periodically.  For many women of color, there is too little information available that helps them understand whether or not they have risks different from other ethnic groups in our population.

 

As scientists and others continue to debate the differing effects of biology, race, and access to care, these types of questions are of too great a practical significance to ignore.  We need solid, dependable information to address some very real and practical questions.

 

 

 

 

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It's Springtime, So Let's Discuss Vitamin D

by Dr. Len April 05, 2006

Springtime is here, and so once again is Vitamin D.

 

You may remember it was about a year ago when a lecture given at the American Association of Cancer Research annual meeting stirred considerable interest when the story was picked up by an astute Associated Press reporter.

 

By May, the newswires, television, and other media were awash with stories that we needed to get more sun to increase our stores of Vitamin D, and reduce our risk of cancer among many other maladies.

 

The fear among many of us was that the story would get muddled, and that a considerable amount of effort that has gone into cancer prevention relative to excess sun exposure would go by the wayside as everyone headed to the beach to increase their vitamin D, their tans, and their sunburns.

 

The main problem was that aside from a handful of advocates, there weren’t many in the scientific and medical community who were prepared to respond to these proclamations, some of which came from recognized and highly regarded researchers.

 

In short, we didn’t have a very clear and cohesive message to tell you what to do, how to do it safely, and what general agreements had been reached on the benefits of vitamin D.

 

It is now another year and we are once again “in season” for vitamin D.  So, buckle up for this lengthy blog of current events on the vitamin D “scene.”

 

A couple of weeks ago I had the honor of participating in a conference in Toronto, Canada which brought together a number of experts in the field of vitamin D, sun exposure, and health. 

 

(We have begun a process to identify consensus statements on what we learned from that conference.  Unfortunately, it is premature to discuss our conclusions, since those discussions are still in progress. I am comfortable discussing my sense of the public presentations at the Canadian conference, since these were public and do not represent the opinions of those currently involved in the consensus discussions.)

 

What did I learn from this conference?

 

First, there is general acceptance that our current levels of vitamin D, as measured in the blood, are too low for general good health.  We are not just talking about cancer here, but we are also concerned about bone health, cardiovascular disease, possibly multiple sclerosis and other illnesses. 

 

My sense is that over time government agencies and others will strive to increase the amount of vitamin D we either “create” from sun exposure or take in vitamin supplements or in fortified foods such as milk and other dairy products.  (I was surprised to learn that the amount of vitamin D we get from milk is minimal, and there is no vitamin D added or present in many other dairy products.  Bottom line: if it isn’t labeled as containing vitamin D, it isn’t there.)

 

Second, there are three basic ways for us to get vitamin D: increased sun exposure, dietary fortification, or vitamin pills. (Look for vitamin D3 in this latter category, since this is the active form.  It is also labeled as cholecalciferol on some bottles.)

 

There are no known adverse effects from fortification or supplements.  However, my dermatology colleagues are caught in the conundrum that increased sun exposure leads to increased risk of skin cancers, both of the fatal type (melanoma) and the usually non-fatal (but potentially disfiguring) basal and squamous cell types.

 

In response to a specific question, some of the experts I rely on indicated that the risk of increased cancer is directly related to the total amount of sun exposure over time, implying that there is no definitely safe daily dose of sun exposure.  Bottom line here is that damage accumulates over time.

 

The conundrum part is that people should be spending time out of doors.  Exercise is good for us, and a “no sun” policy is simply not realistic.

 

All of this sunshine vs. vitamin pills debate is further complicated by the fact that there is not now (and I predict never will be) a one-size-fits-all recommendation for sunshine exposure that will answer everyone’s needs.  (I am having difficulty with those who say a 15 minute walk down the street during the day is adequate to replenish your vitamin D.)

 

Science tells us there are many variables that influence how much vitamin D our bodies will make after being exposed to the sun.  Where you live (think Canada, Maine and Florida), the type of skin you have (burn easily vs. tan without a problem), the amount of skin pigment (fair skinned vs. dark) all influence the amount of vitamin D you will make. 

 

Fifteen minutes of sun can be one person’s dream dose and another’s skin cancer dose.

 

It is simply too complicated to provide a simple recommendation and the risks of long term damage remain.

 

So, for my money, it is going to be supplements and sunscreen.  The risks of the alternatives are too great, and frankly I don’t have the time during the day to go walking around our neighborhood at the opportune times of the day.

 

As to the effect of vitamin D on reducing cancer risks, my sense from listening to the experts is that there really is something there.  There are too many studies with too much data to ignore the suggestion that vitamin D may reduce the risk of developing some cancers.  There is also intriguing evidence that increased levels of vitamin D may improve survival of people who are diagnosed with cancer.

 

Finally, based on what I heard at the conference, we are going to be hearing not only about how much we should increase our intake of vitamin D. There is going to be serious discussion about whether there is a real risk of danger in doing so.  Some experts do not believe that would be a problem.  The current “safe level” of vitamin D intake may well be revised upward in the not too distant future. 

 

And that increasing understanding of what a safe level is, and what levels we should have in our blood, may then lead to making a measurement of vitamin D in your blood as much a part of your annual physical as measuring your blood pressure and your cholesterol.

 

The problem with all of this, if there is a problem, is that this is all based on inferential data.

 

In the past there have been reports about the benefits of various vitamins such as vitamin C, vitamin E, and beta carotene.  When more detailed scientifically controlled studies were done no benefit was found.  In fact, in the beta carotene study which was supposed to reduce the risk of lung cancer in heavy smokers, the exact opposite effect was found, namely MORE smokers who took the vitamin died.

 

The conclusion here is that what seems so obvious is sometimes not so obvious, and requires additional studies to demonstrate whether or not the effects are real.

 

Then this past week, a group of highly regarded epidemiologists from Harvard published a study in the Journal of the National Cancer Institute (JNCI) which was accompanied by an editorial, discussing a research study which tried to look at predictors of vitamin D exposure over many years and correlate that assumption with the risk of developing and dying from a number of cancers. (A technical malfunction on the JNCI website has prevented me from establishing a link at this time.)

 

Today, at the 2006 annual meeting of the AACR there were two more presentations that discussed the relationship of vitamin D to breast cancer risk, and what we need to do to get our vitamin D levels within range of what the scientists claim is necessary to achieve that risk reduction.

 

The article in the JNCI looked at an implied measure of vitamin D based on factors that would probably reflect levels of vitamin D in the blood.

 

Here, the authors followed almost 48,000 thousand men over many years and asked them questions regarding their diets and activities, among other indicators.  For the vitamin D research, they determined that dietary and supplementary vitamin D intake, skin pigmentation, adiposity (fat), geographic location, and leisure time physical activity would reflect higher vitamin D levels in the blood.

 

Those who had higher levels of vitamin D had a 17% decreased risk of developing cancer and a 29% decrease in their risk of dying from cancer.   In particular, for digestive system cancers, there was a 43% decrease in the risk of developing one of these cancers and a 45% decreased risk of death.  Among the cancers with the most significant decreases was pancreatic, esophageal and colorectal cancer.

 

Oral cancers also were fewer in those with predicted higher vitamin D levels.

 

Some other cancers, including leukemia, lung cancer, advanced prostate cancer, renal cancer and non-Hodgkin’s lymphoma were also decreased, but the data were suggestive rather than “significant.”

 

The authors also noted the information reported in the recent WHI study, where blood levels of vitamin D at the time of entry into the study were associated with a decreased risk of developing colorectal cancer in the women who participated in the study.

 

How much vitamin D will achieve this benefit?  I suspect this may differ from person to person, but 1500 units per day is what these experts recommend.

 

And I would be remiss if I didn’t emphasize their comments that African Americans in general may need to be especially aware of this recommendation, since darker skin pigmentation interferes with natural vitamin D prediction.  The authors comment, as have others, that this vitamin D deficiency may in fact explain some of the higher incidence and worse prognosis for African Americans for several cancers.

 

The two abstract presentations from the current AACR meeting are more difficult to comment on because they are just what they are: abstracts.  There is little information in an abstract, and it really represents an early presentation of data from research that is frequently in progress. (To access these abstracts, go to this link--which is a search engine--and enter 4008 for one abstract, and 4009 for the other where it says "abstract number".)

 

Based on the information I have been able to obtain, one study (characterized as “preliminary” by the authors) which measured various physical activities and dietary intake of vitamin D could reduce the risk of breast cancer by about 40%.  Also, these authors suggested that higher vitamin D levels earlier in life were the key to the beneficial effects they observed.

 

The other study looked at a “meta-analysis,” which a statistical way of pooling data from a number of previously reported studies, and concluded that at the highest blood levels of vitamin D compared with the lowest levels there was a 50% reduction in the risk of developing breast cancer

.

The caution here is that the authors state in their abstract that to get to the “good” level of vitamin D you would have to take 2700IU per day which exceeds the current national “safe” intake of 2400IU.  (The press release which accompanied the abstract stated that a woman would have to take at least 1000IU every day.  I cannot explain this significant discrepancy at this time, but 1000IU is certainly easily achievable through a multivitamin containing 400 IU, calcium supplements that are fortified with 400 IU, and a vitamin supplement containing another 400 IU).

 

So that’s the latest information on vitamin D.

 

What should you do?

 

I have tried to outline my thoughts above, but will repeat them here:

 

I don’t think there is harm in increasing your vitamin D intake.  I would be cautious with regard to excess sun exposure, and I would realize that your personal characteristics make this approach a bit chancy in terms of getting the desired effect without getting the undesired harms.

 

I wouldn’t take megadoses of vitamin D, unless you are one of those folks with bad osteoporosis under the care of a physician who understands the benefits and risks of high dose vitamin D (I recently answered the question of a lady who heard that she should be taking several thousand units of vitamin D daily when the doctor meant every several weeks).

 

Whether or not there is real benefit from these recommendations remains uncertain, until more definitive studies are done.

 

But that doesn’t diminish my enthusiasm to move forward quickly in getting clinical trials started where we can best determine what the right level of vitamin D is, and whether or not it really will have the impact on reducing the risks of cancer, or improving the survival of patients with cancer, as has been strongly suggested by the research noted above.

 

++++++++++++++

 

As a “P.S.”: 

 

I pointed out at the Toronto conference that several years ago the same Harvard researchers published a study in the Annals of Internal Medicine that looked at a large number of nurses and found that the vitamin folate also had a significant impact on the reducing the risk of colorectal cancer, if taken over many years.  Despite what appeared to be the same type of evidence we are now seeing for vitamin D, I am not aware that the recommendation to take folate on a daily basis has received much attention.  Yet here is a simple, safe and readily available supplement that may also have a significant impact on decreasing your risk of developing colon cancer if you are a woman.

 

By the way, I did go to a beach during my vacation, and I did use sunscreen, stayed under an umbrella during peak sun hours and wore a hat and a T-shirt.  No sunburn, no tan, but a very nice time with my family.

 

 

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About Dr. Len

Dr. Len

J. Leonard Lichtenfeld, MD, MACP - Dr. Lichtenfeld is Deputy Chief Medical Officer for the national office of the American Cancer Society.

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