A research paper in today’s issue of the Journal of the American Medical Association provides unfortunately impressive evidence that erythropoiesis-stimulating agents, or ESAs, are in fact dangerous to the health of cancer patients.

The drugs, known by their trade names Procrit and Aranesp, have been the focus of intense scrutiny by patients, patient advocates, researchers, the press, politicians, the Centers for Medicare and Medicaid Services and others for much of the past year.

The current report, authored by a group of researchers from many well-regarded universities, shows that without a doubt ESAs lead to a much higher incidence of venous thromboembolism when patients treated with these drugs are compared to those who are not treated with ESAs.

The paper also reports that survival is shortened for cancer patients treated with ESAs, although the results are not quite as dramatic.

ESAs have been important drugs in the treatment of patients with cancer. 

They first came to market in the early 1990s.  For those of you who aren’t familiar with cancer treatment at that time, we had great concerns about the safety of the blood supply.  Transfusions will always have risks, but in those years the risks were magnified by the fact that we didn’t have very effective ways of  ensuring that the blood supply was as safe as it is today.

ESAs came along and helped address a serious problem, namely that we could use these drugs to boost a patient’s hemoglobin, or red blood cell count, without resorting to transfusions.

That was the reason the FDA approved these drugs, but over the years things got a bit out of hand.

Back when ESAs were first approved by the FDA in 1989, and we would transfuse a typical patient if their hemoglobin was 10 or lower (or perhaps a bit higher than that if they other serious underlying conditions such as congestive heart failure or coronary artery disease), then why not use ESAs to boost the blood level even higher?

And if 11 was good, why wouldn’t 14 (essentially a normal value) be better?  And if 14 was better, wouldn’t all cancer patients feel better if they had a boost from using these drugs, even when they weren’t on active treatment with chemotherapy or radiation therapy and their anemia was due solely to their underlying cancer?

You can begin to understand what happened.  The use of these drugs expanded far beyond their original intent.

Along the way, direct-to-consumer TV advertising became a hit and ESAs were right there in front of you every day and night on the TV shows where older patients and those most likely to develop cancer would be watching.

Apparently, some physicians got in on the game to an even greater degree, taking “rebates” for prescribing the drugs.

Unfortunately, no one bothered to take a closer look at the extensive off label use of ESAs, whether that off-label use was justified by strong clinical evidence, and what the side effects may have been under that circumstance.

Then last year, the Cancer Letter published an article revealing data from a clinical trial which suggested that cancer patients who were treated with ESAs did not fare as well as those who did not receive these drugs.  To say that those reports were shocking would be an understatement.  Few if any anticipated that outcome.

That’s when the snowball started rolling, and eventually we came to the point where an FDA advisory panel raised serious concerns about continued use of these medicines.

The result is the type of research article we are discussing here today.

What does this mean?

In plain terms, when used as directed, these drugs put cancer patients who received them at about a 57% increased risk of deep vein thrombophlebitis and possibly pulmonary embolism w(hich occurs when a blood clot breaks off from a clot that forms in the veins of the legs and travels through the circulation into the lung).  When large enough, these clots can lead to sudden or near-immediate death.

Cancer doctors know that DVT and PE are a risk for many cancer patients as a result of their underlying disease.  ESAs, as shown by this research, increase that risk significantly.

Secondly, the researchers report that ESAs increase the risk of death in cancer patients by about 10%. 

The report also discusses an emerging body of research that shows some cancer cells have receptors for ESAs on their surface that may result in ESAs causing an increase the cells’ cancer-related properties.  If that’s the case, and if the experiments translate into real life, that would mean that the use of these drugs could enhance cancer growth at the same time the doctors are using other drugs to control the disease.

To say the least, this is not a pretty picture.

The FDA is going to have a follow-up advisory panel meeting in mid-March to review the new data.  I wouldn’t be surprised if they raise even more serious concerns about the value of these drugs and how they should be used in the treatment of cancer patients.

The Centers for Medicare and Medicaid Services recently issued rules on the use of ESAs that have been considered very draconian by many, putting into place significant limits on their use.

I suspect that we are going to see more of that type of control put into place by the FDA, the recognized professional societies that make guidelines recommendations on the treatment of patients with cancer, and the insurers who pay for this treatment.

We may also see an increased scrutiny of off-label uses of medications, which is where much of the ESA use occurred. 

For patients, it means that your doctor is likely going to become more conservative in recommending and using these drugs.  At the least, you and your doctor need to have a clear understanding of indications, benefits and risks of using ESAs in your cancer treatment.  You need to have that conversation with your doctor, who ultimately knows you and your medical condition best.

It doesn’t mean that these drugs should not be used in anyone, just that we must be more careful and cautious.  (I should note that ultimately the recommendations on indications for the use of ESAs are going to come from the FDA, and this blog has been written well in advance of the FDA’s comments and actions in response to this and other new research.)

Ultimately, if we are going to improve the quality of our medical care, we need to understand how these situations come to pass. 

It isn’t just ESAs that have raised questions like this.  Hormone replacement therapy (HRT) is another example of a widely used treatment that has undergone significant pullback once we had a better understanding of its benefits and risks.

The ESAs are valuable drugs, and probably do have a role in clinical medicine and in the treatment of patients with cancer.  Just like HRT, there will be a lot of scrutiny, followed by a significant pullback in their use, and then likely a more balanced approach to the use of these agents in appropriate patients in appropriate circumstances with appropriate discussion between doctors and their patients.

But we can’t forget that there are a lot of people who promoted these drugs, who administered these drugs, and patients who either expected or demanded to be treated with these drugs. 

The question we really need to ask ourselves is: Why did this happen, and how do we prevent this from happening again?

If we fail to scrutinize what we did and how we did it, we are destined to repeat the same mistakes again and again.

That, my friends, is not acceptable.

The FDA’s decision late Friday afternoon to provide “accelerated approval” for the use of Avastin in the first line treatment of HER-2 negative metastatic breast cancer was the culmination of a lot of handwringing and head scratching on the part of many people.

From my vantage point, the FDA made the right decision in a difficult situation.  That said, this is not the end of this story.

I have previously written about Avastin and the decision of an FDA advisory panel several months ago to (closely) vote not to approve the drug for this indication.

That decision by the panel members had to be a difficult one.  Metastatic breast cancer is a disease that is treatable, but not considered curable.  Every time we have a new drug that may offer benefit to women in this circumstance, it is important that we make certain that we are providing an effective therapy that will indeed help those in need.

The Avastin situation is of interest for a number of reasons.

When determining if new cancer drugs are effective, the FDA generally wants to see evidence that the group treated with the drug lives longer than the group that receives the standard therapy.  In this case, Avastin was added to the chemotherapy drug Taxol, a well established and effective drug in the treatment of metastatic breast cancer.

Unfortunately, based on the data available at the time of the panel review, Avastin did not improve survival of the women who received it to an acceptable degree.

What it did do was double the time until the disease progressed from 5.8 months in the women who received only Taxol, to 11.3 months in the women who received Avastin in addition to Taxol.

Nagging questions remained when the FDA advisory panel had to make its recommendation. 

For example, it may have taken longer for the disease to progress with Avastin treatment, but were the women better off during that time?  There was no evidence presented which objectively supported that their quality of life had improved.

That said, most oncologists either in their own experience with Avastin (it has been used “off label” by oncologists pending the FDA review) or their experience in similar circumstances found it hard to accept that delayed progression would not be associated with an improvement in function and quality of life.  However, the data wasn’t available to support that opinion, and we have learned all too frequently recently that expert opinion may not equate with objective facts.

The other issue was that there were more serious side effects seen in the women taking Avastin compared to those who received the standard chemotherapy alone.

All of that information considered, I did note in my December blog—popular commentary to the contrary—that there had been other biologic drug approvals recently based on increasing the time to progression, and not limited solely to improved survival.  The approval of Tarceva in the treatment of women with HER-2 positive metastatic breast cancer was such an example.

So, as I mentioned above, in my opinion the FDA on Friday did the right thing by granting this conditional approval.

There is still more work and analysis to be done.  As noted in a Genentech (the company that makes Avastin) press release,http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11027 the company has agreed to provide the FDA with data from ongoing trials.  The company wrote that review of this data—which is expected to be available by late 2008—will be needed before this accelerated approval can be converted into a full approval. (Interestingly, I cannot find an announcement on the FDA website at the time I wrote this Monday morning.)

Before everyone celebrates, however, we must remember what happened with another targeted therapy called Iressa, which was initially approved by the FDA in 2003 for the treatment of lung cancer.

That drug also had a secondary review, and based on additional study findings, the FDA had it removed from the market in 2005.  Although the Genentech data is promising, there is no guarantee that the same thing could not happen here.

But the alternative of not approving Avastin, in my personal opinion, would have created a worse situation. 

Avastin in the treatment of metastatic breast cancer is not inexpensive.  Had the drug not been approved, I would not have been surprised if insurers vigorously opposed its off-label use or made the co-pays so onerous that only the wealthy could have afforded it (there is no guarantee that that won’t happen under the current scenario with approval).

In its press release, Genentech did indicate that it will provide Avastin free of charge to any woman who exceeds 10,000 mg of the drug in a 12 month period.  They go on to say that the cost for 10,000 mg is approximately $55,000 wholesale.   Given mark-ups at the retail level, one can’t get past the fact that this is an expensive drug—as are many other new, targeted therapies.

As a point of reference, the dose of Avastin in the clinical trial was 10 m/kg on days 1 and 15 of each course.  For a “typical” 154 pound/70 kg woman, that would translate to roughly 1400 mg of Avastin per 4 weeks.  The 10,000 mg “mark” would be reached about 7 months into treatment (28.6 weeks, to be exact).

Medicare Part B (fee for service) currently allows $57.46 for 10mg of Avastin.  The cost for our “typical” patient $57460 at Medicare rates before the free medication offer would be available.  Medicare covers 80% of the drug’s cost under Medicare Part B.  With a 20% co-pay for drugs administered under Medicare part B, that would translate into an out-of-pocket cost for the drug in the amount of $11,492, not considering benefits available if a patient had co-insurance to help cover the costs.

What we have here is a confluence of circumstances that point out several of the difficult issues we must face as patients, oncologists and as a country.

First, the approval of Avastin in the treatment of HER-2 negative metastatic breast cancer does appear--based on the current evidence--to be a significant step forward.  We hope that the additional trial data will support and expand the benefits of this truly remarkable drug.  At the same time, we must reserve some caution that this drug can have serious side effects, and it is important for patients and their doctors to have full, open and honest communications about the benefits and risks of the therapy.

Second, we have to develop clear and understandable guidelines for clinical trials in cancer treatment so that we don’t continue to run into these situations with the FDA where we must make what I call “Solomonic” decisions based on less that than the best evidence.  Avastin in breast cancer is but one example of the controversies surrounding the drug approval process that must be resolved going forward.

Third, we can’t ignore the fact that many of our new cancer treatments are very expensive.  Without affordable access to care, we are going to create a multi-tier system of medical care with the best care available to a few and a lower standard available to everyone else.

The American Cancer Society has declared its position on affordable, accessible health care as a key in moving our efforts forward to diminish the burden and suffering from cancer.  Breakthrough drugs and new indications for those drugs highlight how important it is that we address access to care now, before we suffer the consequences of our inactions.

In the meantime, thousands of women will hopefully benefit for this treatment, and that is something we should all celebrate.

Every year around this time the American Cancer Society publishes its annual “Cancer Facts and Figures.”  This year, the report is being released today, February 20^th. 

You may not know the name of the publication, but you may well be familiar with its content.  This is the report that is so frequently quoted in the media as the source of a statement which is something to the effect, “According to the American Cancer Society, “x” number of people will be diagnosed with (type of cancer) in the United States in 200x, and “y” number of people will die from that disease.”

The reason this report is so important is that it provides us with an update in how we are doing in our nationwide fight against cancer.  It provides an estimate of the incidence and deaths of cancer in 2008, based on the best available information from years past.

This report also provides us an opportunity to get a sense of where we are headed in our efforts to eradicate cancer as a fatal disease.  And, each year, we select a particular topic to focus on which will provide us an in-depth analysis of a particular problem related to cancer, such as pain or the relationship of infections to the causation of various cancers. 

Perhaps the most watched statistic in Cancer Facts and Figures is our assessment of the number of cancer deaths year to year.

You may recall that for the past two years we reported there were actual declines in the number of people who died from cancer from 2002 to 2003, and 2003 compared to 2004.  In fact, last year we reported that there were over 3000 fewer cancer deaths when comparing 2004 to 2003.  (The reason for the delay in determining the number of cancer deaths 3 years previously has to do with the time it takes to get accurate information.)

At the time, we said we hoped the trend would continue.  But we also cautioned it may not.  After all, it takes many years to define a continuing trend, and variations from year to year can be hopeful or disappointing, but they may not define on ongoing direction.

This year, we report that from 2004 to 2005, there was an increase of 5,424 deaths from cancer in the United States.

What that means is that there was a smaller decline in the cancer death rates during 2005 which were not enough to overcome the large increase in the number of people at risk of dying from cancer.

That may sound a bit confusing, so let me try to explain.

The population of older people is rapidly increasing in this country as baby boomers age.  Age is probably the most significant risk factor for cancer.  When we have more people at risk, we would expect to see larger numbers of deaths.

That is counterbalanced by the rate of cancer deaths.  If the decline in death rates is large enough, it can overcome the negative effects of the larger, older adult population.

In two previous years (2002 to 2003 and 2003 to 2004), that was the case.  The rate of decline in cancer deaths was large enough to overcome the increase in the number of people at risk of developing and dying of cancer.  For those years, the rate of decline for each year was about 2%.  From 2004 to 2005, however, that was not to be.   For that year, the rate of decline slowed to 1%.

But that doesn’t mean we have not been making progress, nor does it mean that in years to come we won’t once again see an absolute decline in the number of cancer deaths.

Take a look again at the rate of decline and what you see is that the rate of cancer deaths declined by more than 5% over that period of time from 2002 through 2005.  To me, that is a remarkable number.

For example, colorectal cancer death rates declined about 6% from 2003 to 2004, and another 3% from 2004-2005.

Here is another way to look at the progress we have made:

When you look at the rates of cancer deaths from 2004 and compare it to those that were seen in 1990-1991, the estimate is that over half a million deaths from cancer were averted during that time period.  Over that interval, death rates from cancer decreased by 18.4% among men and by 10.5% among women.

To me, that is an astounding number.  If we were not doing anything different for the prevention, early detection and treatment of cancer, we would have lost an additional one-half million people during those 15 years. 

There are some other numbers worth noting in this report.  Unfortunately, not all of them are good numbers.  But we should never ignore the fact that there is much we could be doing better and more effectively.

In men, prostate, lung and colorectal cancer account for ½ of all cancer diagnoses.

For women, breast, lung and colorectal cancer make up 50% of new cancer diagnoses.

We have much to learn about the detection and treatment of men with prostate cancer, and we don’t know much about how to prevent the disease. 

We do know how to prevent some breast cancers in women at high risk, and we certainly know a considerable amount about how to find the disease early. 

We know how to prevent lung cancer, are learning  whether or not early detection is a real possibility, but we can’t do much to treat the disease in most people once it has been diagnosed at an advanced stage or spread through the body.

Colorectal cancer is to me the leading example of our frustration at truly decreasing the burden of cancer, when you consider the real and almost immediate impact we could have on deaths from this disease if we only did what we know works.  Literally thousands of lives could be saved every year if people got screened for this disease in accordance with American Cancer Society guidelines.

I have previously reported on our Annual Report to The Nation, where we discussed the dramatic decline in breast cancer deaths from 2001 to 2004.  And I also pointed out that although there is some hope regarding lung cancer in women, the sad reality is that deaths from this disease have increased slightly each year from 1995 through 2004.

In African-Americans, the toll of cancer remains overwhelming.  African-American men have a 19% higher incidence rate and 37% higher death rate from all cancers combined when compared to white men.

On the other hand, although African-American women have a 6% lower incidence of cancer compared to white women, but their death rate is 17% greater.

Some of this disparity is undoubtedly due to the focus topic of this year’s Cancer Facts and Figures, namely the role that insurance (or lack thereof) plays in delayed diagnosis and treatment of cancer in this country.

Again, this is not a new topic.  Even as recently as this Monday my colleagues at the American Cancer Society have published another of several articles demonstrating how lack of insurance or adequate insurance adversely impacts the outlook of many people in this country with cancer.

Access to care impacts prevention, early detection, diagnosis, treatment and outcome of people with cancer.  We cannot ignore that fact, and this year’s Cancer Facts and Figures once again outlines the enormity of the problem that faces us in this country.

So, as is often the case we have some news to celebrate, and some news that is not so good.  We have areas were we have excelled, and areas where we have not.

But, as always, we must keep looking forward, improving on our successes and turning around our failures.

By constantly striving to improve—through more research, better application of what we know, and making certain that every citizen in this country has access to a health care system that is the most technologically advanced in the world—we will eventually achieve success in reducing the suffering and burden of cancer.

This is not an easy task, and it is not a simple or quick one.  But I remain an optimist that we can achieve our goals, continue to see declines in cancer incidence and death rates, and continue to present annual Cancer Facts and Figures reports that document our progress.

Last Friday the Food and Drug Administration (FDA) announced there is an increasing probability that the smoking cessation drug Chantix is associated with the onset of new, serious psychiatric symptoms.  That raises a number of questions that could impact the use of this effective medication.

I can't say that I am surprised.

Chantix—also known by its generic name varenicline—was approved by the FDA in May 2006 to help smokers quit. 

Unlike other medications used to help people stop smoking (such as nicotine replacement products in the form of patches, gums and sprays, or an anti-depressant called Zyban--also known as Wellbutrin), Chantix works in a unique way by blocking nicotine receptors in the brain.

The initial research reports in the Journal of the American Medical Association indicated that Chantix was more effective in helping smokers quit when compared to placebos and Zyban.

When studied in over 1000 “generally healthy smokers” who took Chantix for the prescribed 12 week course, 21.9% of the people who used Chantix were still not smoking at one year compared to 16.1% of the participants who took Zyban and 8.4% of the people who used a placebo.

In a companion report where researchers evaluated people who had successfully stopped smoking on Chantix after the initial 12 week treatment course, they found that if they gave another 12 weeks of “maintenance” Chantix, they found that 43.6% did not resume smoking compared to 36.9% who received a placebo.

The results were applauded, and Chantix quickly became a mainstay in the treatment of smoker’s who wanted to quit.  That was notwithstanding the fact—as pointed out in an editorial that accompanied the publication of the articles in JAMA—that these reported results were likely going to be better than what would be found in the general population once the medication was marketed to the smoking public.

As with any newly released medication, there are always cautions.  It is not uncommon for potentially serious side effects not previously seen in clinical trials to become evident after new medicines are used by many patients once the FDA approves them for release.   

I actually made some statements to that effect in my blog at the time.  I noted then that the clinical trials which evaluated Chantix were conducted in relatively healthy smokers, a group that really doesn’t represent the many current smokers who have several serious chronic illnesses.

In that same blog, I highlighted depression as one of those serious medical conditions for a very specific reason. 

I had heard in a pre-market briefing that patients with depression and other serious medical and psychiatric illnesses were not included in the clinical trials.  In fact, I specifically asked about this during that briefing, to make certain that my understanding of the information provided at that time was correct.

When you have a drug that acts on the central nervous system, and possibly influences the very same chemical signals that may have a role in depression, wouldn’t it be logical to assume that this particular drug may have some possible effect on that interaction?

Because of these concerns, I provided a link to the FDA’s MedWatch in the blog, where unanticipated possible side effects could be reported.

So it came as little surprise a couple of months ago when a report surfaced suggesting that a bizarre change of behavior in a rock singer which led to his death may have been linked to Chantix.

That got the ball rolling, and the FDA subsequently released an advisory on November 20, 2007 indicating that they had received reports of suicidal thoughts, aggressive behaviors and drowsiness in some patients linked to Chantix.  They indicated that they would be working with the drugs manufacturer to evaluate these reports and issue further guidance.

In January, the company announced that they were putting a warning label on Chantix.

That warning highlighted “serious neuropsychiatric symptoms have occurred in patients being treated with Chantix.”

The warning went on to say that this may be related to smoking withdrawal itself, but some of the patients who experienced these symptoms had been continuing to smoke while taking Chantix.  The symptoms included changes in behavior, agitation, depressed mood, suicidal ideation and suicidal behavior.”  Worsening of pre-existing psychiatric illness was also noted as a possible effect of the drug.

I was also not surprised to see the following in the new warning:

“Patients with serious psychiatric illness such as schizophrenia, bipolar

disorder, and major depressive disorder did not participate in the pre-marketing studies of CHANTIX and the safety and efficacy of CHANTIX in such patients has not been established.” (Emphasis mine)

This past Friday, the FDA posted another advisory.  This, time, they said that it is “increasingly likely that there is an association between Chantix and serious neuropsychiatric symptoms.”

What is the bottom line for patients and their doctors who are trying to decide whether or not to use Chantix as part of smoking cessation efforts?

I can’t give specific medical advice in this column.  I can say that Chantix appears to be an effective aid in helping people to quit smoking. But, like every medication, it has some risks. 

It is important for patients to understand those risks, and for their family, friends and health care professionals to be alert to those risks and act accordingly.  You can’t ignore someone who is becoming newly depressed or more depressed when they take this medication.  You must act immediately.

That said, there are other alternatives to help you stop smoking such as nicotine replacements mentioned above.  There is also Zyban, but this drug also has side effects you need to know about.

If you are contemplating stopping smoking, check out the information on our website, or call us at 800-ACS-2345.  Talk with your doctor or other health care professional and decide what steps are right for you.

You may choose to start with something other than Chantix first, and then move up to that medication if your efforts are not successful.  Or, you may want to go directly to Chantix. 

I can’t tell you that there is a “right” or “wrong” approach. But I can tell you that you need to be aware of these warnings and the risks. 

The chances are these numbers of adverse events are going to be small, but we don’t know that yet. 

What is clear is that they are real, and a source of concern.  They must be taken seriously by patients and doctors alike.