Twenty years ago, Surgeon General C. Everett Koop wrote, “The right of smokers to smoke ends where their behavior affects the health and well-being of others.”

Today, the current Surgeon General, Richard Carmona, MD, emphasized that statement and added evidence to the argument that secondhand smoke, or involuntary exposure to tobacco smoke, has severe health consequences. 

His report released this morning and titled “The Health Consequences of Involuntary Exposure to Tobacco Smoke” is thorough and hard hitting, with a clear message.

The evidence cannot be overlooked: secondhand smoke kills, secondhand smoke harms, and secondhand smoke has no safe limit of exposure.

And, according to the Surgeon General, the only effective strategy to reduce the adverse health effects of secondhand smoke is to remove it from our work, home, recreational and hospitality environments.  Anything less than a complete ban simply won’t work.

We have come a long way over the past four decades regarding our knowledge of the harms of cigarette smoking.  There likely aren’t many folks who aren’t aware of the dangers of smoking cigarettes, and for many who do smoke there are many who try repeatedly to quit.

We haven’t been as effective in convincing everyone that second hand smoke is also dangerous to our health, but we have made some progress over the past twenty years since the release of the last Surgeon General’s report which specifically addressed the harms of second hand smoke. 

We still have a long way to go, according to the evidence presented by Dr. Carmona.

Probably the most important messages from the Surgeon General’s report which was released today are what they call the “Major Conclusions.”

Here they are, with some of the points highlighted by me for emphasis:

• Second hand smoke causes premature death and disease in children and in adults who do not smoke

• Children exposed to secondhand smoke are at an increased risk for sudden infant death syndrome (SIDS), acute respiratory infections, ear problems, and more severe asthma.  Smoking by parents causes respiratory symptoms and slows lung growth in their children.

• Exposure of adults to secondhand smoke has immediate adverse effects on the cardiovascular system and causes coronary heart disease and lung cancer.

• The scientific evidence indicates that there is no risk-free level of exposure to secondhand smoke.

• Many millions of Americans, both children and adults, are still exposed to secondhand smoke in their homes and workplaces despite substantial progress in tobacco control.

• Eliminating smoking in indoor spaces fully protects nonsmokers from exposure to secondhand smoke.  Separating smokers from nonsmokers, cleaning the air, and ventilating buildings cannot eliminate exposures of nonsmokers to secondhand smoke.

If those are the only points you remember from the extensive scientific review and documentation contained in the report, then you understand enough to realize that this thorough analysis makes the exceptionally strong case for smoke-free environments essentially a no-brainer.

In addition, there are no rational arguments left to oppose smoke-free environments, or to speak against the legislation and regulation required to make them happen in communities across this nation.

Dr. Carmona talked about the fact that many people think that if they have only a little exposure there is no harm.

Not so, he pointed out. 

The Surgeon General was emphatic in his press conference this morning that secondhand smoke is harmful, and the effects are immediate. 

The effects on the cardiovascular system of secondhand smoke on non-smokers can be almost immediate.  If you have coronary artery disease, and you are a non-smoker (perhaps you are a former smoker) and you enter a smoke filled environment, the adverse effects of the second hand smoke in the environment can have an instantaneous effect on your body, your health and maybe even your life if it triggers a heart attack.

The report cites estimates that there about 46,000 excess deaths annually from cardiovascular disease and 3400 excess deaths each year from lung cancer related to secondhand smoke.

I think you will agree that these are not trivial numbers, and each life is a universe of its own, precious to those who know and love the people who die prematurely and unnecessarily (that, in plain English, is what the scientists mean when they say “excess deaths”).

The Surgeon General also takes on the tobacco companies and others who have used tactics that are, shall we say, less than open and honest.

Let me quote some interesting comments from the report:

“The evidence on secondhand smoke and disease risk, given the public health and public policy implications, has been reviewed extensively in the published peer-reviewed literature and in evaluations by a number of expert panels.  In addition, the evidence has been criticized repeatedly by the tobacco industry and its consultants in venues that have included the peer-reviewed literature, public meetings and hearings, and scientific symposia that included symposia sponsored by the industry.  Open criticism in the peer-reviewed literature can strengthen the credibility of scientific evidence by challenging researchers to consider the arguments proposed by critics and to rebut them.

“Industry documents indicate that the tobacco industry has engaged in widespread activities, however, that have gone beyond the bounds of accepted scientific practice.  Through a variety of organized tactics, the industry has attempted to undermine the credibility of the scientific evidence on secondhand smoke.  The industry has funded or carried out research that has been judged to be biased, supported scientists to generate letters to editors that criticized research publications, attempted to undermine the findings of key studies, assisted in establishing a scientific society with a journal, and attempted to sustain controversy even as the scientific community reached consensus.”

These are harsh words to be sure, but perhaps the circumstances demand that level of discourse.

We know secondhand smoke is bad.  60% of the citizens of this country have evidence in their bodies of exposure to secondhand smoke.  Our homes are becoming the primary places where this exposure occurs, and 126 million workers are still subject to secondhand smoke in their workplaces.

What more do we need to know? 

What more do our political leaders at the local, state, and national levels need to hear to understand the issue? 

Help me understand what more we can say, what more we can do, what more we can study to prove that smoking is bad not only for the smoker, but for everyone around them (including their spouse, who has a 25% greater chance of getting lung cancer than if they lived with someone who did not smoke)?

Let’s face the facts: even this administration, which is clearly pro-business, has produced a document which says the only way to produce a safe environment is to ban smoking from the building.

No fans, no ventilators, no separate rooms for smokers, no bars where kids can’t eat—NOTHING has been shown to reduce the levels of secondhand smoke to a safe level of zero except getting it out of the building completely.

That, to me, is the key message of the report and it is one that the Surgeon General emphasized clearly in his press conference this morning.

The science is overwhelming, the business case is overwhelming, and the human impact is overwhelming.

I guess I am perhaps a bit angry that it has taken us this long to get to where we are.  At the same time, we shouldn’t ignore the progress that has been made. 

But this stuff is bad, we know it’s bad, and I wonder how much more effort and time will have to expended to convince those that lead, and those that vote, that secondhand smoke is bad for everyone.

I suggest that we take a close look at the overwhelming evidence in the Surgeon General’s report, and make it very clear that the time for excuses is over, and the time for action is now.

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Aside from the many tobacco-related activities the American Cancer Society is engaged in, we also have a sister advocacy organization arm called the Cancer Action Network. 

Go to their website for more information, and send a letter to your elected officials about your concerns related to smoking and secondhand smoke in your local community.

I apologize for the lapse in recent postings.  Lots of travel and other obligations have kept me busy in other areas of responsibility.

This week should be more interesting, with the Surgeon General’s report on second hand smoke due out tomorrow.  Next week is some short vacation time for July 4^th, but the week after that will be a busy one with the 2006 International Cancer & Tobacco Control Conferences in Washington DC.

Before I forget, if you have the opportunity, tune in to Discovery Health Channel tomorrow (Tuesday) evening at 9PM EDT.  The program is titled “Relay for Life: Giant Steps” and it talks about the importance of the American Cancer Society’s Relay for Life through the eyes of cancer survivors and their families.  I found it to be very moving, and I hope you will as well.

About 10 days ago the New England Journal of Medicine published two articles and an editorial about some exciting advances in the treatment of chronic myelogenous leukemia.

It wasn’t just the research that got my attention.  It was the implications attached to the research that were captured in the accompanying editorial that show once again we are in a new era of cancer treatment and drug discovery.

It wasn’t so many years ago that we were very excited about a new drug called Gleevec which revolutionized the treatment of chronic myelogenous leukemia, commonly known as CML.

Gleevec was a targeted therapy which basically blocked the cancerous white cells in CML from producing a protein that helped the cancer cells become, in a sense, immortal.

When patients were treated with the drug, both those in early and advanced CML, the results were nothing short of spectacular.  Responses were immediate, were effective, and enabled people to recover quickly from their disease with only reasonably limited side effects.

The drug worked best in patients with early stage CML, and continues to work very well for many folks in that group. 

However, as is the case with many cancers, the CML cells in some patients developed resistance to Gleevec and the disease progressed.

That’s what these two research reports in the NEJM were about.

Because we have learned so much about how CML cells work and how we could target them for treatment, scientists were able to take that same knowledge and apply it to the treatment of patients where there cells were resistant to Gleevec.

It may sound simplistic (it’s not simple, promise) to say that two groups of drug researchers were able to find other places to target the workings of the CML cancer cells.  But that is what they did, and the result is that both of the new treatments were effective in patients who had either failed Gleevec or were not able to tolerate the therapy.

Once again, the patients were the beneficiaries and have had significant responses to both drugs (one is called dasatinib and the other nilotinib).

It remains to be seen whether either or both of these drugs will be used in place of Gleevec, or with Gleevec in a drug cocktail that may be more effective than either drug alone similar to what is done with multiple antibiotics or AIDS treatments where the different drugs have different effects on the infectious bacteria or viruses.

Why is this so important? 

It’s not just that we have two potential lifesavers for patients with CML.   

As pointed out in the editorial by Dr. Brian Druker, who had a major role in the “invention” and application of Gleevec, there are three reasons why we are so impressed with these studies.

First, these drugs provide another treatment option. 

Second, as Dr. Druker noted, the research once again highlights the value of what we have learned about how cancer cells work, how they become resistant to chemotherapy, and what we can do to overcome that resistance.

But it is the third observation that makes this so impressive: these drugs were conceived, developed and tested in a short period of time that was, up until now, unthinkable.  It is somewhat akin to breaking the four minute mile.

As I have listened to lectures over the past several months, I continue to be amazed at the speed with which targeted therapies are identified and put into clinical trials.  I have heard investigators indicate that they have more drugs to test in clinical trials than patients willing to participate in clinical trials. I have heard how investigators at major cancer centers, who formerly may have had a “friendly competition” to be the first to test a new drug or combination of drugs, have come together to work on joint studies to move drugs from the bench to the bedside faster and more efficiently than has ever been accomplished in the past.

There was another observation made by Dr. Druker that I also found of interest.

One of the questions that has bothered me for some time is how we will continue to afford the development of these targeted therapies, when we realize that the targets in cancer cells are many, but the patient population who may benefit from each targeted therapy is small.

A case in point may be the therapy of lung cancer with certain targeted drugs.  Of the patients treated with these drugs, only 10% may benefit.  The benefit may be great for those people, but for the vast majority there is no effect on the disease whatsoever.

Since the population that benefits is so small, the cost of the drug must be high to offset the investment made in developing the drug and bringing it to market.

Dr. Druker asks the question of why large companies would make investments in drug development under these circumstances, when the potential return on their investment is small in comparison to what they can make by developing an effective drug for much more common illnesses.  After all, the American Cancer Society estimates there will be only about 4500 cases of CML diagnosed in this country in 2006.  That pales in comparison to the millions of folks with heart disease, diabetes and hypertension.

His response to this dilemma is that by understanding the “science” behind the cancer cell, drug companies have a higher likelihood of developing an effective drug much like the situation with the two new drugs discussed above.  The risks and costs of failure are reduced.

In addition, instead of testing the drugs on large numbers of patients—which is very costly—the researchers can focus their efforts on a smaller number of patients whose cancers have the specific “target” under investigation.

Finally, because the target is clear, and the patient population well defined, the drugs may move through the regulatory process more quickly since the results will be more clear cut and rational.

I don’t know if Dr. Druker’s hypotheses are correct or not, but they are interesting.  Time will tell whether one of the additional side benefits of our cancer research successes will be more expedited, focused drug development and clinical testing resulting in more rapid “pass through” of new drugs to patients who need them.

As I have said before, we are living in revolutionary times when it comes to cancer treatment.  And it certainly is something positive to contemplate when we talk about successes built upon successes in such rapid sequence, compared to what we have experienced over the past many decades.

The major health news today is that the FDA has approved a new vaccine which will prevent many cases of cervical cancer.

The vaccine, called Gardisil and developed by Merck, has been approved for administration to girls ages 9 through 26 who have not begun sexual activity.

In my opinion, this development is transformational for medicine and medical practice, and will have a substantial impact on the health of women in this country and elsewhere.

9710 women expected to be diagnosed with cervical cancer in this country in 2006, and it is expected that 3700 women will die from this disease. 

What is truly remarkable is that there are going to be over 1.5 million women in the United States who will be diagnosed with pre-cancerous lesions of the cervix that require the follow-up and possible treatments I mentioned above. 

The cost of treating cervical disease each year in this country is approximately $3.5 billion dollars, not to mention the loss of productivity and anxiety associated with these diagnoses and treatments.

Gardisil has the potential to reduce deaths from cervical cancer throughout the world, which is critically important since cervical cancer kills about 288,000 women worldwide every year.  It is the second leading cause of cancer death in women outside of the United States, especially in underdeveloped countries who cannot afford extensive cervical cancer screening programs.

This vaccine also has the potential, over the next several decades, to substantially change the way we provide healthcare to women.

Much of women’s gynecologic healthcare is focused on cervical cancer screening, and dealing with the results of what are effective tests (for example, the PAP smear) which can produce confusing results.

Aside from the anxiety associated with those abnormal results, there are the real issues of the follow-up and procedures that are done to find out whether or not the test was significantly abnormal or whether more extensive treatments including surgery are required to prevent a pre-cancerous lesion in the cervix from progressing to a frank cervical cancer.

Over the past several years, researchers were able to demonstrate that HPV causes cervical cancer, and they have been able to identify which viruses are closely associated with the development of cervical cancer

There are many types of HPV viruses, and they are transmitted by sexual contact.  Almost everyone who is sexually active gets these viruses—both men and women—but it is only a very few who develop any problem as a result of the virus. 

For most of us, it goes away and doesn’t cause a problem.  But, for some, the problems can be serious and include cervical cancer and genital warts.

The current vaccine includes 4 types of HPV viruses.  Two of these virus types are related to cervical cancer, and the other 2 to genital warts.

We know that another vaccine is in testing which contains just the two HPV viruses that cause cervical cancer, but it wouldn’t be unexpected to see additional viruses added to both vaccines over time.

Right now, the estimates are that Gardisil will be able to prevent about 70% of cervical cancers, and about 90% of genital warts.  But to be most effective, based on current evidence, it has to be given before women become sexually active.  There are ongoing studies to determine whether booster doses will be necessary at some time after the primary series of 3 shots within 1 year is completed.

Not to be ignored were research results presented this week at the American Society of Clinical Oncology meeting where Gardisil was also demonstrated to decrease the incidence of vulvar and vaginal cancers in women.  Although these cancers are much less frequent, they can be devastating for women who are diagnosed with them.

Interestingly, this is not the first vaccine that is known to prevent cancer although it is the first vaccine specifically designed for that purpose.

Hepatitis B vaccine has been shown to reduce the risk not only of hepatitis, but also primary liver cancer (called hepatoma).  In some parts of the world, primarily Asia, where the incidence of hepatitis B and liver cancer are high, there have been dramatic reductions in liver cancer as a result of widespread immunization programs in young people.

I can recall years ago having discussions with my colleagues about what we called the “viral theory of cancer.”

After all, we reasoned, if cats could be vaccinated and protected against feline leukemia virus, why would it such a stretch of the imagination to think that the same thing could be done for humans?

We were a bit premature in our optimism, although there has been and will continue to be considerable research into the question of whether viruses (and bacteria, for that matter) cause other cancers besides liver cancer and cervical cancer.

Although there was some circumstantial evidence in the past that cervical cancer may have had an infectious cause, or could be transmitted by some other agent related to sexual activity, it was still a pleasant surprise when research honed in on HPV as the cause of cervical cancer. 

That gave researchers the opportunity to target the virus and begin work on the vaccine which has culminated in its approval today. 

It was not without a considerable amount of hard work, research support (including funds from the American Cancer Society) and financial investment that enabled us to reach this goal.

Our hope is that over time further research will not only expand our knowledge regarding HPV and cervical cancer, but also provide insights into the etiologies of other cancers where a vaccine “strategy” may prove effective in preventing disease.

The vaccine may not be related to an infection, but could also be the result of expanding knowledge into what targets on the cancer cell could be detected and “killed” by an antibody our bodies could produce in response to a vaccine.

Just this week an article was published in the prestigious Proceedings of the National Academy of Sciences describing a vaccine which targeted angiogenesis (growth of new blood vessels in tumors) and slowed tumor growth in mice.  It did this through targeting a receptor on the surface of a cancer cell that is involved in angiogenesis.

Granted that mice are not men, and that it is a long way from basic research into developing a concept that actually works in treating patients.

But just imagine the impact if we were able to make a vaccine that would target similar proteins and receptors on cancer cells before they become visible?

That may sound like the stuff of dreams, but I’m not certain that such a goal cannot be achieved.

So what we have today is a definitive major step forward in our efforts to reduce the burden and suffering from one form of cancer.

Our hope is that this is just the beginning, and that the future will bring many more such advances.

Time will tell.

Yesterday I posted a commentary on the STAR Trial presented at the ASCO meetings.

One of the issues that has received considerable attention in discussions about this trial is the importance of the increased risk of uterine cancer as a determining factor in which drug--raloxifene or tamoxifen—is a better prevention strategy for post-menopausal women who have a high risk of developing breast cancer.

But there is another factor that has received somewhat less attention, and that is the observation that the women taking tamoxifen had over twice as many hysterectomies during the trial compared to women who took raloxifene.  There was no clear explanation for this difference, according to the researchers.

Maybe I can shed some light on the reasons for this, and why this may be an important consideration for women who are contemplating taking one of these medications to decrease their risk of breast cancer.

First, a bit of background.

Tamoxifen is a drug that has been used for over 3 decades.  During that time, it has had a remarkable track record of helping women who had recurrent, hormone-sensitive breast cancer.  Subsequently, it has also proven effective as an adjuvant therapy in both pre-menopausal and post-menopausal women in preventing recurrence of breast cancer after primary treatment.  It has meaningfully increased survival rates from this disease.

Over time, it became apparent that tamoxifen had some undesirable side effects, including an increased incidence of deep vein thrombophlebitis (blood clots usually in the veins of the legs) and pulmonary embolism (blood clots that break off and travel to the lungs, and which can be a life-threatening situation).

However there was one side effect in particular that was most troublesome, and that was the increased risk of uterine cancer associated with long-term use of the drug.  In one study, the risk of developing uterine cancer was 2 ½ times greater in the tamoxifen treated women compared to women taking a placebo, or “fake” pill.

Understanding this concern, the researchers closely followed the incidence of uterine cancer in women taking tamoxifen on the STAR trial compared to the women in the same trial who were taking raloxifene.

There were 19,747 postmenopausal women who participated in the STAR trial.  As I have mentioned previously in yesterday’s blog entry, one half of the women took tamoxifen and one half took raloxifene.

To my surprise, a little over half of the women in each group had had a hysterectomy prior to entering this study.  Although this seems high to me, I have no information to say whether this is typical for most post-menopausal women or not.

The implication of this fact, however, for the purposes of this discussion is that in the comments below we are essentially focusing on about 5000 women in each group who could have possibly developed uterine problems during their treatment with either tamoxifen or raloxifene while on the STAR trial.

Now, to the heart of the question: are there real differences between the two drugs and their effects on the uterus that women need to consider as they make their choice of preventive treatment with either raloxifene or tamoxifen?

36 women taking tamoxifen and 23 women taking raloxifene developed invasive uterine cancer during the course of their therapy on the STAR trial.

Looked at another way, for every 1000 women treated with tamoxifen, 2 women out of 1000 at risk (that is, with an intact uterus) on tamoxifen developed uterine cancer each year, compared to 1.25 women per 1000 at risk each year on raloxifene.

In plainer terms, for each year on treatment, for the approximately 5000 women on tamoxifen there were an average of 3.75 more cases of uterine cancer each year in the tamoxifen treated women compared to the raloxifene treated women (10/year with tamoxifen, and 6.25 with raloxifene).

(I should point out here that there is no evidence that raloxifene increases the risk of uterine cancer in this or prior studies.)

When looking at the data graphs provided in the articles published in the Journal of the American Medical Association, the difference in the incidence of uterine cancer between the two groups of women actually doesn’t begin to become evident until after 4 years of treatment on the drugs.

Here is the hooker: the difference between the two drugs with respect to the risk of uterine cancer is not statistically significant, which means that one cannot say with complete confidence that tamoxifen definitely increases the risk of uterine cancer compared to raloxifene. (For those scientists among you, the P value is 0.07.) 

However, based on past experience with tamoxifen, one would have to err on the side of caution and say that these data are certainly suggestive of a difference in favor of raloxifene. 

But the analysis shouldn’t stop there.

What was significant about the effects of the drugs on the uterus was that there was a clear and definite increase in uterine hyperplasia, both with and without atypia, in the women taking tamoxifen.

For a better understanding of this issue, I had to turn to my “in-house” gynecology expert, who happens to be my wife.

Hyperplasia refers to a proliferation, or thickening, of the cells lining the uterus.

In a post-menopausal woman, when this occurs, it can lead to the sign of post-menopausal bleeding. (By the way, whenever this happens and you are post-menopausal-- whether you are a woman taking tamoxifen or not-- it is critically important that you see your physician as soon as possible.)

When the doctor examines the uterus and takes a sample of the tissue, it can usually show one of three things: normal (without atypia), atypia, or cancer.

Normal means normal.  There is no evidence of cancer or pre-cancer.  Atypia is another word for pre-cancerous changes.

If the doctor finds cancer, then a hysterectomy is the next step.  The same goes for atypia.

In the STAR trial, there were 84 women on tamoxifen who had hyperplasia of the uterus found during the course of their treatment, compared with 14 women on raloxifene.  This difference was substantial and very significant.

Of the 84 women on tamoxifen with hyperplasia, 72 were normal on biopsy and 12 had atypia.  Those 12 likely had a hysterectomy, which is the appropriate treatment according to my consultant.

For the women on raloxifene, there were only 14 women who developed hyperplasia.  Of these women, 13 were normal on biopsy and 1 had atypia.

Going back to our “how many per thousand women treated” analysis, this essentially means that each year there were probably about 3.1 more hysterectomies for atypia in women taking tamoxifen compared to the women on raloxifene (3.35 hysterectomies per year for the 5000 women on tamoxifen and 1.25 for the 5000 women on raloxifene).

Now we get to a very interesting observation: There were over twice as many hysterectomies performed for reasons other than cancer on women taking tamoxifen compared to women taking raloxifene during the course of the study.

The actual numbers of hysterectomies done for reasons other than uterine cancer were 244 in the tamoxifen group, and 111 in the raloxifene group.  Again, this difference was impressive, and clearly statistically significant.  It is very likely a real difference between the two drugs.

But why such a big difference between the two groups?  Why would doctors be doing so many more hysterectomies on women taking tamoxifen who had no evidence of cancer or pre-cancer in their uterus? (During the presentation at ASCO, the comment was made that the reason for this huge discrepancy was not clear.)

That is the question I posed to my wife.

Now, I must caution you that this is one doctor’s interpretation but it makes medical sense to me.  And although I can’t back this up with data from the study, it may be an important consideration for you if you and your doctor are trying to make your minds up about which drug to take.  (I would also point out that the data below are from the actual published research paper, so they are reliable.)

My wife pointed out that the gynecology community is very sensitive to the uterine cancer risk of tamoxifen.

Although post-menopausal bleeding is not a rare syndrome, in the gynecologist’s experience when it occurs in a post-menopausal women taking tamoxifen it has added significance and importance.  The byword here is caution, especially in a woman who is usually taking tamoxifen because she has already had the diagnosis and treatment for a primary breast cancer.

So, when the doctor evaluates the patient for abnormal bleeding and she is on tamoxifen, even though the uterine biopsy may be negative for atypia or cancer, there remains a high level of concern that there may be cancer somewhere else in the uterus that was not “sampled” through the biopsy.

The net result is that combining the woman’s past history of breast cancer and her use of tamoxifen, even though the uterine biopsy is negative for any suggestion of cancer or pre-cancer, the doctor is going to be much more conservative and recommend a hysterectomy.  They want to be certain they are not missing the small chance that there may be some small area of cancer elsewhere in the uterus in this woman at higher risk because she taking tamoxifen.

Mind you, as I said, this is a practical explanation for the observation of increased hysterectomies in the women in the STAR trial treated with tamoxifen.  It is not based on a detailed analysis of the literature.

But if you are a woman at high risk of breast cancer who wants to take tamoxifen and you have not had a previous hysterectomy, the chances you will have a hysterectomy are about twice as high on tamoxifen compared to raloxifene.  So, each year in the STAR trial, among 5000 women in each group, there were approximately 68 hysterectomies for reasons other than cancer in the women taking tamoxifen, compared to about 30 in the women taking raloxifene.

In my opinion, these are significant numbers and worthy of consideration in this discussion.  The differences here are greater than any of the other side effects reported in this trial, and have real impact when we talk about the risks of hysterectomy with its own set of difficulties (such as hospitalization, cost, time off of work).

One final point is critical in this discussion: I probably would not have been going into this great a detail if I thought one drug was clearly better than the other.

What has stuck in my mind has been fact that although both drugs are equivalent in terms of decreasing the risk of invasive breast cancer for post-menopausal women at high risk,  tamoxifen appears to also decrease the risk of non-invasive breast cancer (DCIS and LCIS), and raloxifene does not.  At least that is what prior evidence has suggested.

In the STAR trial, the trend was in favor of tamoxifen being more effective in this regard, but again the data was very close to significance, but it didn’t cross the magic line where we would have considerable confidence that there was a real difference P value=0.052).

In fairness, one of the ASCO presenters made an argument based on his analysis that in fact there was no real difference regarding a reduction in the risk of non-invasive cancers.

But to me, this is a real concern since non-invasive cancers, although fortunately almost always curable, do require treatment and do reflect increased risk for the patient developing another invasive cancer at a later date.  That is the main reason why I think there are tradeoffs between the two drugs, and neither was clearly superior to the other.

So what did the published data show in this regard, using the same type of analysis I have provided above?

In total, measuring both DCIS and LCIS, there would be about 7.5 non-invasive breast cancers per year in the 5000 women treated with tamoxifen who still had an intact uterus, and 10.5 non-invasive cancers for the 5000 women on raloxifene who had an intact uterus.

So, for women who still have their uterus intact and where the questions about uterine cancer would still be significant, there would have been about 3 fewer non-invasive cancers in the tamoxifen group compared to the raloxifene group (again, focusing only on those women who had not had a prior hysterectomy).

That compares to an extra 3.75 cases of uterine cancer and 3.1 cases of atypia (both requiring hysterectomies) each year, and an extra 38 hysterectomies in the women taking tamoxifen compared to the women taking raloxifene.

So that is the equation of the “trade-off” between the two treatments in somewhat absolute, stark terms: 3 fewer cases of breast cancer, compared to about 45 more hysterectomies, of which 7 will be done for cancer or pre-cancer of the uterus.

I don’t know how one makes a choice between these two options. 

If your fear of uterine cancer is high, or your fear of gynecologic surgery is similarly elevated, then raloxifene would be your best bet.  If you fear breast cancer, then tamoxifen might be your consideration.  If you have already had a hysterectomy, then this part of the “toxicity” discussion is of no meaning to you since you are not at risk of uterine cancer.

As the investigators mentioned in their presentation, they are planning on continuing to follow these women.  Perhaps some clarification will develop over time that will help sort out these questions further.

Until then, this information will hopefully give you something to use in discussions with your physician.

Several weeks ago, prominent researchers announced the results of a large clinical research trial called the STAR Trial (for “The NSABP Study of Tamoxifen and Raloxifene P-2 Trial”).

This trial was designed to find out whether a drug called raloxifene, which is commonly used to prevent and treat osteoporosis, was as effective as a drug called tamoxifen in preventing breast cancer in women at high risk of developing this disease.

The enthusiasm of the researchers who spoke at the news conference that the “new drug” (raloxifene) was clearly superior to the “older drug” (tamoxifen) resulted in numerous articles and comments by experts that perhaps their excitement was perhaps a bit premature.

Yesterday, at the annual meeting of the American Society of Clinical Oncology, some of the questions about the trial were answered.

But I still don't think we have a clear "winner." 

We have known for about 7 years that tamoxifen, a drug that first became available in the mid-1970’s for the treatment of recurrent breast cancer, is effective in reducing the incidence of breast cancer by about 50% in women who have a high risk of developing breast cancer, based on a number of factors.

More recently, raloxifene (trade name: Evista) was also found to reduce the risk of breast cancer in studies that were primarily designed to examine its effects on osteoporosis.

As a result of those findings, another study was started in 1999 to look at a head-to-head comparison of the two drugs.  The goal of the study was to determine whether either drug was better than the other in reducing the risk of breast cancer in post-menopausal women at high risk.  The study was also designed to look at a number of other factors as well, including symptoms, tolerability, uterine cancer, and blood clots among others to find out whether one drug had more or less problems than the other.

In mid-April, I reported the results which were presented at that news conference.  Although the doctors clearly indicated that they thought raloxifene was the superior drug in this trial, I wasn’t so certain and said so.

Yes, both drugs were equal in preventing invasive breast cancer.  But tamoxifen was better at preventing non-invasive breast cancer (called DCIS and LCIS).  At the same time, there were fewer cases of uterine cancer in the women who took raloxifene, but the numbers were not statistically significant which meant that although they appeared to be different, there remained a slight possibility that the finding could have been due to chance.

There were other issues as well, as I described at the time.

My bottom line recommendation was that until further information was presented for analysis in a more standard fashion (such as a presentation at a major medical meeting or published in detail in a medical journal), women would do best to consult with their physicians before they chose one drug over the other.

(In fact, tamoxifen is approved for use as a breast cancer prevention treatment for women at high risk, while raloxifene is not.  But many doctors already prescribe raloxifene for the treatment of osteoporosis, so it wouldn’t be that difficult—with full informed consent—for a doctor to prescribe the drug “off-label” as part of a breast cancer prevention strategy.  My educated guess is that the company which makes raloxifene—Eli Lilly—will likely file an application for the new indication in the not too distant future.)

We finally had our wish fulfilled yesterday when the papers were presented at the ASCO meeting, at the exact same time they were published on-line by the Journal of the American Medical Association.

So what did we learn from this new, much more detailed information?

Most importantly, both drugs are equally effective in reducing the risk of breast cancer in women at high risk (I keep emphasizing the “high risk” part of that sentence.  There is no evidence that raloxifene prevents breast cancer in women at average risk, and to make that assumption would be, in my opinion, incorrect.  I would not recommend raloxifene for the prevention of breast cancer unless a post-menopausal woman has a measured increased risk of 1.66% of developing breast cancer over the next 5 years as determined by her “Gail score”).

When women were asked about their overall sense of physical health, well-being and depression among other factors, there was no clinically significant difference between the two drugs in their answers. 

Women on tamoxifen had better sexual function but more gynecological problems, vasomotor symptoms (hot flashes and sweats), leg cramps and bladder control problems. 

Women on raloxifene had more musculoskeletal problems, pain on intercourse and weight gain.

Neither drug was better than the other when it came to fractures.

There were also no differences between the two drugs with regard to the frequency of other cancers, coronary artery disease events, or stroke.

But there were some differences.  There were more cataracts and cataract surgeries in the women who took tamoxifen.  There were more episodes of deep vein thrombophlebitis and pulmonary embolisms (blood clots to the lungs) in the tamoxifen group than the raloxifene group.

Slightly over half of the women in both treatment groups had had a hysterectomy before starting this trial.  In women who had not had a hysterectomy, there was a suggestion that tamoxifen caused more uterine cancers (a known side effect of the drug).  It clearly caused more premalignant changes in the uterus, and there was a significant increase in the number of hysterectomies performed on women taking tamoxifen compared to those on raloxifene.  The reason for the increase in hysterectomies is not clear, except for the small number related to cancer (36 in the tamoxifen group and 23 in the raloxifene group).

Perhaps one of the more important questions that isn’t clearly answered by the study is which drug is better at preventing what we call “non-invasive” breast cancers (DCIS and LCIS).

These are usually small cancers that are found on routine mammography.  The cancer does not invade the milk duct, and generally can be treated by local surgery and radiation, followed by consideration of tamoxifen as an adjuvant therapy.

Although not life-threatening as a general rule (there are exceptions), they do result in a significant increase in the risk that the women with this diagnosis may develop invasive breast cancer at a later date.

There was a clear trend, just shy of statistical significance, that tamoxifen was better than raloxifene at reducing the frequency of these cancers.

As the researchers reported in their presentation, the impact of this difference remains unclear.  They plan to continue following the women to see if there is any real, practical difference in outcomes as a result of this differential effect.

(Why there should be a difference is another interesting question.  Both drugs are similar in the way they work.   Why both would be effective in preventing invasive breast cancer, while only one would be better at predicting non-invasive disease remains a mystery.)

Why is all of this important?

As we all know, breast cancer is a serious illness.  We have known for several years that there is a medicine available that will reduce the frequency of the disease in post-menopausal women who are at high risk.  But women (and their doctors) don’t seem to want to take the medicine or prescribe it.

If we had a medicine that women and their doctors trusted, so goes the thinking, then more women will take advantage of the opportunity to do something for themselves.  Since raloxifene is a drug frequently used and trusted by primary care doctors and gynecologists, then wouldn’t it be logical that they would be more willing to prescribe it and women more willing to take it?

I’m not so certain the situation is that simple.  As with everything else, the circumstances are usually more complicated than they appear at first glance.

For example, I wonder how many primary care doctors really understand “risk” of breast cancer and risk prevention strategies. 

If they do understand it, how many have the time (except in the most obvious of cases) to suggest to their patients they consider taking a medicine for prevention of a disease, when the actual numbers of women who would benefit is small for any particular woman?

Then there is the question of what side effects a woman is ready or willing to accept as part of a prevention strategy.

If you are feeling well, how much risk are you willing to take that you will develop uterine cancer, cataracts, or a blood clot in the legs or the lungs?

The recent Vioxx experience suggests the answer is “not much” for many people.

In fact, about 96,000 women were preliminarily screened and considered eligible to participate in this study, and only about 20,600 agreed to move forward to the more detailed screening process.  Perhaps for many of these women, the side effects of both drugs was more than they wanted to consider.

In addition, about 3/10 women who took either drug (and were probably initially highly motivated) dropped out of the trial, which is likely a lower dropout number than would be the case in the general population of women.

The difficulty in medicine is that it is sometimes as much art as science.  It is sometimes not as clear cut as we would like.

We occasionally have reports of new treatments that are so compelling they can change the standard of practice overnight.  In fact, there were a couple of reports at the current meeting that will likely do just that.  The data is very clear in providing guidance that we need to move on to the new treatment.

Or, the data may be very clear that the new treatment is not effective, which is equally important.

But what do you do when the drugs are basically equivalent, and each has its advantages and disadvantages?  What do you do when one of my trusted colleagues says that tamoxifen and raloxifene “are like Coke and Pepsi” when it comes time to make a recommendation on which one is better?

There was an editorial that accompanied the JAMA articles published online.  The comments of the editorialists were, in my opinion, very insightful.

“Although media coverage of the early release of data from the STAR trial suggest a clear ‘winner’ in raloxifene, the data from clinical end points and patient-reported symptoms suggest a less clear conclusion…

The breast cancer chemoprevention sky now includes 2 shining STARs—tamoxifen and raloxifene.  Although neither is a supernova, their benefits include prevention of breast cancer in postmenopausal women at increased risk and, in the case of raloxifene, reduction of fractures related to osteoporosis.  Perhaps because the clear benefits are limited to these end points, the relatively modest adverse event profiles and minimally impaired quality of life experienced by these women still may not be enough to convince primary care physicians to be more aggressive than they have been to date in breast cancer chemo-prevention.  Time will tell.”

Some of my readers have indicated they expect me to make a recommendation about which drug is best for them based on the evidence.

I don’t want to disappoint you, but there is no single recommendation that applies to every post-menopausal woman at high risk of breast cancer as to which drug is better.  Your doctor is still your best guide as to what is right for you.

But I do have some suggestions for you to consider, based on what I have read and what other doctors have said.

First, know your risk score.  If it is 1.66 or higher, talk to your doctor about your options. 

If you decide to proceed with therapy, weigh the risks and benefits of each drug as outlined above. For example, if you have had a hysterectomy, tamoxifen may be a better choice for you since it appears to have a greater benefit of reducing both invasive and non-invasive breast cancer, and you don’t have to be concerned about developing cancer of the uterus. 

And if one drug doesn’t work for you, then you know that you now have another option.

I know that these recommendations are not definitive.  Sometimes medicine is like that.  But I can’t say something the evidence doesn’t prove, and in this situation there are real pluses and minuses for both drugs.

I think it is also important to remember that these drugs do not prevent every breast cancer in every woman at high risk. 

We have taken another step in journey, with a long way to go.  We have another option which may provide more women with a chance to take advantage of a proven strategy to reduce their risk of breast cancer.

What I can say, with confidence, is that I don’t think researchers, women, their families and many others are going to rest quietly until we have a much better understanding of what actually causes breast cancer and what we can do to prevent it with a drug or other approach that in fact is an obvious winner to all of us.

So much can happen in a year, or so it seems when listening to the presentations currently underway at the annual meeting of the American Society of Clinical Oncology in Atlanta.

At last year’s gathering, the news that Herceptin (trastuzumab) reduced the recurrence of breast cancer after primary treatment in a select group of women whose tumors had a gene called HER/neu2 was greeted with unprecedented cheers and applause from the thousands of cancer specialists in attendance.

This year, the chair of the session which reviewed the current state of knowledge on the use of Herceptin and similar drugs as treatments for breast cancer in the adjuvant and recurrence settings made a startling statement.

The doctor, Eric Winer MD, noted that much progress has been made in this area over the past 10 years.  Looking forward, he noted, he anticipates over the next 5 or 10 years that we will be looking back at women with this particular type of breast cancer and realize that they will be the first group of cancer patients where our research resulted in an almost complete reduction in deaths from this disease.

That is a bold statement, and I personally am not certain that this prediction will come true.

But who will argue if we are able to reduce the recurrence rate of this form of breast cancer by, let’s say, 75% instead of 100%?  The reality is that through many decades of research, we are in the process of reaping great rewards for our patients who suffer from these terrible illnesses.

I was impressed last year by the number of new treatments reporting successes using an increasing number of new drugs called targeted therapies.  My impressions remain unchanged this year as we begin to hear the results of the continuing strong interest in and apparent successes of these new types of drugs, which actually target the processes in the cell that make a cancer cell cancerous.

There are many such targets, and understanding those targets and the development of drugs taking advantage of that knowledge is continuing at a rapid pace.

For example, in the same symposium yesterday where Dr. Winer made his prediction, there was a brief discussion of another paper that was actually presented earlier today.

In this study, the researchers looked at the effectiveness of a new targeted drug called lapatinib in combination with an existing oral chemotherapy drug called capcetibine in the treatment of women who have HER/neu2 breast cancer that has continued to grow despite treatment of metastatic disease with Herceptin.

What is interesting is that lapatinib targets the same breast cancers in women where Herceptin (trastuzumab) has proven effective.

But, although these drugs have the same basic target in the breast cancer cell, Herceptin targets a location on the surface of the cell.  Lapatinib actually gets inside the cell and targets the processes inside the cell.

The result is that for these women with this particular genetic marker we now have two drugs which effectively block the same cancer cell processes.

The results reported yesterday and today indicate that this new combination of capcetibine with lapatinib, when started after the cancer progresses while a woman is taking Herceptin, can effectively prolong the time it takes for the recurrent breast cancer to progress from 19.7 weeks on capcetibine alone  to 36.9 weeks with the combination of the chemotherapy drug with the targeted therapy.

That may not sound like much, but remember that these are “medians”, which means half the women took less time to progress than stated, while half took longer.   But remember that this is in women with advanced breast cancer, and for some of the women the delay in progression is much greater than 36.9 weeks.  And, with the new drug, the time measured was almost doubled.

When we make progress in the treatment of cancer, that progress has usually been one step at a time—not through giant leaps (although that has been occurring with greater frequency over the past several years).  So this increase of about 17 weeks—or 4+ months—is indeed an important element of progress for a group of women where just a couple of years ago the outlook was exceedingly bleak.

It also doesn’t take much thought to realize that by combining these two drugs there may be even more benefit, especially in early treatment in the adjuvant setting.  Also, combining these targeted therapies with other targeted therapies that have different targets may further increase the benefits already seen from each of these drugs separately.

In fact, another speaker at yesterday’s symposium indicted that such studies are underway or are planned for the near future.

The message here is that we are making real progress.  In fact, from my perspective, the pace of progress is exceedingly rapid.  There are a number of new agents that appear to have significant promise, and getting these drugs studied in the clinical treatment of cancer patients is going to be increasingly challenging.

From where I sit, all of these new drugs and new approaches to treatments can be confusing and difficult to sort out.  But that is a problem that many of us are glad to confront, because it offers real hope to so many people either living today with cancer, or those who will inevitably confront this disease in the future.