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Have We Learned The Lessons Of The ESAs?

by Dr. Len April 30, 2009

Two articles published this afternoon in the Lancet and the Canadian Medical Association Journal once again remind us that just because something looks good in cancer treatment doesn’t mean it is good, and may actually cause harm.


You may remember the controversy that surfaced a couple of years ago about medications called ESAs which were (and continue to be) used to boost the red blood cell counts of patients with cancer.


What did today’s studies report that has me so concerned?  Basically that there was no situation—whether or not patients were on active chemotherapy or whether they were simply being treated for anemia associated with their cancer—where these drugs did not increase the risk of death. 


As the story unfolded at the time, it appeared that these medicines not only improved anemia in cancer patients, but also increased the risk of death.  There was a considerable outcry, guidelines from respected medical organizations were quickly changed, Medicare put definitive treatment guidelines in place, and the Food and Drug Administration eventually changed their guidance on how the drugs could be used.


Now, two years later, we have these new reports that take the story one chapter further, and may be the end of these drugs in routine practice, barring special circumstances.


The Lancet study was particularly well done.  Internationally recognized experts in study design and analysis identified a number of research trials where these drugs were administered to increase red blood cell counts.  The trials included those performed by the companies that manufactured the drugs, as well as others run by investigators not affiliated with the drug companies. Basically, these trials compared patients who were treated with the ESAs to patients who did not receive the drugs but were given blood transfusions when needed.


After identifying the studies, the researchers went back and were able to obtain the actual patient records for almost 14,000 patients.  They looked at the risk of death while the patients were being actively treated and at their overall survival.


Bottom line, the patients who were under active treatment with ESAs had a 17% greater chance of death if they received the ESAs compared to the patient who received blood transfusions.  Overall survival for all patients was significantly decreased as well.  It didn’t make much of a difference, according to the authors, whether or not the patients were on active treatment for their cancer, although the increased rate of death was a bit less if a patient was receiving chemotherapy as opposed to other treatments for their cancer such as radiation therapy.


There was a greater increase in deaths for patients who started with more severe anemia.  There was a lower rate of deaths in patients who had prior thromboembolic events, such as deep vein thrombophlebitis or pulmonary embolism.  The reason for this was unclear, and it is possible that those patients were on blood thinners that may have prevented new blood clots from forming.


The authors concluded:


“The findings of this individual patient data meta-analysis show that erythropoiesis-stimulating agents increase mortality in all patients with cancer, and a similar increase might exist in patients on chemotherapy. Most randomised trials and previous meta-analyses have shown that erythropoiesis-stimulating agents increase haemoglobin concentrations, reduce the need for transfusions, and reduce fatigue. In clinical practice, the increased risks of death and thromboembolic events should be balanced against the benefits of treatment with erythropoiesis-stimulating agents, taking into account each patient’s clinical circumstances and preferences.”


The Canadian study took a more traditional approach to this question, through carefully studying and combining the published information from several research papers that met pre-determined requirements.


These investigators essentially came to the same conclusions: use of ESAs decreased survival, in large part because of an increased incidence of what we call “thrombotic events,” namely deaths related to blood clots traveling in the body, usually into the lung (pulmonary embolism).


However, this study pointed out that ESAs did decrease the need for blood transfusions and did increase the quality of life for patients who received them.


Their conclusion was essentially the same as the investigators in the Lancet paper:


“Use of erythropoiesis-stimulating agents in patients with cancer-related anemia improved disease-specific measures of quality of life and decreased the use of blood transfusions. However, use of the agents led to an increased risk of all-cause mortality and serious adverse events. We found no evidence that the risks or benefits of treatment differed among patients who did or did not meet recently revised criteria for the use of these agents in patients with cancer. Our findings suggest that existing practice guidelines should be revised to recommend against the routine use of erythropoiesis-stimulating agents as an alternative to blood transfusion in patients with anemia related to cancer.”


So what are we to conclude from all of this discussion?


First and foremost, these studies basically sound a warning that the use of these medicines in any patient with cancer—whether or not they are on active treatment—should be preceded by a detailed discussion of the benefits and the risks, understanding that the risk of death from the treatment is not some abstract theory.


If you decide to use ESAs, you will be balancing the risk of an “adverse event” against the possibility that it may in fact improve your quality of life.  That improvement comes at a cost: possibly shortening your life.


It is clearly no fun to have to get a blood transfusion.  But it is less fun to have an embolism and all of the associated consequences, which include the possible loss of a life.


There is also a larger story here, and that is the question of how we got here in the first place.


These medicines have been around a long time.  They were one of the first “biologic therapies” that entered active clinical practice back in the late 1980’s and early 1990’s.  They came on the scene when we were very concerned about the safety of the blood supply.  At the time, they were hailed as a scientific miracle.


Their use grew and grew and grew.  More and more patients received them, including for off-label indications without evidence to support some of that use.  Doctors were willing to give them, and some doctors pushed the envelope aiming for higher and higher red blood counts because they said that patients felt better.  The costs of these drugs to various reimbursement programs such as Medicare went up and up and up.


All this while some doctors were encouraged to use these medicines through incentive programs that included rebates, which in one well documented situation amounted to millions of dollars.


And then, clues started to appear that maybe these drugs weren’t as safe as everyone thought they were.


This is the type of experience that should give all of us pause.  We should know as much as possible about the drugs we use to treat patients, including cancer patients where we are willing to accept more risks than in otherwise healthy patients, given the serious nature of the disease.


We can’t always get to “truth” on these issues, but we need to do a better job of asking the right questions at the right time.  Who knows how many people have had their lives shortened because we failed to ask those questions?  Who knows how much harm has been caused?


We should take the lessons of ESAs, embody those lessons, and try to move closer to the truth of what we do, understanding both the benefits and the harms of the treatments we offer. 


Just because someone has cancer, and may be near the end of their days, doesn’t mean that we should ignore the evidence and not help people make informed decisions at what is arguably the most difficult time of their lives. 


Filed Under:

Cancer Care | Medications | Treatment

Provenge A Winner, Questions Remain

by Dr. Len April 28, 2009

The results are as predicted: the prostate cancer vaccine Provenge (sipuleucel-T) prolonged survival in men with hormone –resistant prostate cancer, but didn’t do anything to delay progression of the disease.


The results of a clinical trial studying this controversial vaccine were released this afternoon at the annual meeting of the American Urological Association in Chicago, and the news wires are already humming with the news.


Unfortunately, I still don’t have access to the actual abstract and have to rely on a news release from the company that ran the trial, which is not always the most satisfactory way for me to get information.  Once I receive the abstract, I may update my comments if there is any significant new information.


According to the press release, 512 men participated in the trial.  They were men who had prostate cancer that had progressed and was no longer responding to hormonal manipulation or medications.  They were asymptomatic, which does put them in a better risk profile for long term survival, but this was true both for the men who received the vaccine and received a placebo.  The study measured the overall survival of the participants.


For the men receiving Provenge, their survival was increased by 4.1 months compared to those who received the placebo (25.8 months vs. 21.7 months).  31.7% of the men receiving Provenge were alive at 3 years, compared to 23.0% of the men who received placebo.  Side effects were reported to be very modest.


All of these results were statistically significant, which suggests that the results were not due to chance.


Unfortunately—and to me this is the unusual part of the trial--the vaccine did nothing to delay the progression of the disease.  Vaccine or no vaccine, the time to progression was the same.  Despite no delay in progression of the disease, survival was prolonged.


As mentioned in my previous blog, based on my interpretation of comments made in a prior conference call, these results are in line with past studies of this vaccine.


So what are the implications?


The treatment of advanced prostate cancer hasn’t made much progress in the past many years.  There are some chemotherapy drugs that help, but they have significant side effects and don’t do much to improve survival.  There aren’t many other alternatives out there—such as targeted therapy—that have received much notice for effectiveness in treating this very difficult-to-treat disease.


But we also have to remember that for several cancers the progress in treating the disease over the past 30 or 40 years hasn’t come in one big jump, but rather is the incremental advance of a couple of months here with one drug, and with another couple of months there with another drug.


As I mentioned in my prior blog, this report also advances a theory that has haunted many researchers and clinical investigators for years, namely how to create a vaccine from tumor cells that can harness the body’s own immune mechanisms that fight off viruses and bacteria (and probably small numbers of cancer cells that must exist in our bodies) to attack a cancer that has escaped from our own internal surveillance system.


Provenge has now broken through that barrier, and suggests that we may in fact be able to stimulate our body’s own defense mechanisms to aid our fight against cancer.  This in itself is a truly remarkable accomplishment.


In the midst of this promise, I would be less than honest if I didn’t say that there are still some potential pitfalls.


First, as I mentioned a couple of weeks ago, this is a “top line” analysis of the results.  A more detailed analysis and publication of the results—not to mention review by the FDA—still must be done.


There has been some background “noise” suggesting that there may be something about the way the men on the placebo arm were treated that may have influenced their survival adversely.  Although this is unlikely—and difficult to prove—there is some chatter to that effect.  That’s why the review of the data is so important. 


The support for that concern can be found in the fact that the vaccine did nothing to delay progression of the disease.  Usually, the situation is the other way around: the new drug delays progression of the disease, but may not increase survival.  The normal way we think suggests that delay of progression is necessary before you see a survival benefit.  That did not happen with Provenge.  So, did the men who receive the placebo have something happen to them that may have shortened their lives compared to those who received Provenge?  It isn’t likely, but it is possible.


That also leaves open to question whether or not the quality of life of the men who had their lives extended was also improved by the vaccine.  Sometimes clinical trials measure quality of life (such as appetite, weight loss/gain, bone pain, ability to function, among others), sometimes they don’t.  I don’t know whether or not quality of life was looked at in this trial.  But it isn’t much of a life that is extended in intense pain, poor appetite, and wasting away.


All of these thoughts are speculation on my part, but offered in an effort to look beyond the headlines into the questions that will be asked by others as the data is reviewed. 


The sooner we can see all of the data from the study, the sooner we can move forward with getting this drug to men who need it if it indeed meets the expectations that have been set with the release of today’s results.


That would be true progress.

Progress In Cancer: Glass Half Full Or Half Empty?

by Dr. Len April 24, 2009

The article in today’s New York Times by reporter Gina Kolata has a lot of truth, and perhaps a bit of misdirection.


It seems that we are hearing more and more about the lack of progress in treating cancer, or the failures of prevention and early detection.  I’m not certain what is driving this sudden spate of articles in several highly regarded media venues, but it must be acknowledged as an obvious topic of interest.  Otherwise, reporters wouldn’t be reporting it. At the same time, I also believe that we must put these discussions into balance and context. 


It is undeniable that we have made progress in the prevention, diagnosis, and treatment of cancer.  At the same time, we need to acknowledge the harms of our treatments and the limitations of our capabilities.


First, the concern: the article suggests that we have made little if any progress in reducing cancer deaths in this country since 1950, in contrast to dramatic declines in deaths from heart disease, flu and pneumonia. 


A true statement, but maybe a bit misleading.  It suggests no progress in reducing cancer deaths. Our top epidemiologist at the American Cancer Society, Dr. Michael Thun, says that’s like visiting base camp at Mount Everest before and after an ascent and concluding nothing had changed. It ignores the remarkable feat accomplished in the meantime.


There was a dramatic increase in cancer deaths from 1950 to 1990, in no small part due to our addiction to tobacco.  As well, it took significant time to build the cancer research infrastructure that is now producing significant improvements in our understanding of how cancer works, and how we can design treatments that are beginning to attack even some of the cancers that have had the poorest prognoses.


As a result of that work, cancer death rates peaked in the late 1980’s and early 1990’s.  Since then, there has been an 18% decline in cancer death rates for men, and a 10% decline in cancer deaths for women.  The American Cancer Society estimates that we have avoided 534,500 deaths from cancer that would have otherwise occurred if we had made no progress from the cancer death rates we were seeing in the early 1990’s.  That is not “no progress.”


It is true that common forms of cancer—once they spread—are not curable.  But to say that survival has not improved is not true.  There have been increases in survival in recurrent breast and colon cancer.  We haven’t made much progress in lung and prostate cancer.  Our treatments have improved survival in certain cancers and are lacking in others.  


(The lack of progress in treating advanced disease may be the difference between looking at statistics for people who initially present with advanced cancer, compared to those whose disease progresses after primary surgery, radiation and/or chemotherapy.  This may seem like a subtle comment, but it is significant in terms of the way cancer behaves.)


Another point in the article was the comment that there are those who claim that all you have to do is eat right, exercise and get screened and avoid cancer. 


I think it is fair to say that if you adopt healthy lifestyles you reduce your cancer risk.  Research does confirm that observation.  But it doesn’t prevent every cancer.  And not every breast or colon or cervical cancer can be found early with screening.  Also, finding every cancer early doesn’t guarantees a “cure.”  It is also fair to say that in the lifestyle war—such as obesity—we are not winning the fight.  That is a counterbalance to some of the progress we have made in cancer, and other diseases including diabetes, hypertension and heart disease.


Cancer isn’t like heart disease or pneumonia.  It is more subtle, more insidious, and not by any stretch of the imagination a single disease.  It doesn’t cause a pain in your chest (until frequently too late) or send you to the emergency room for immediate treatment.  We don’t have pills to generally reduce your risk, such as a blood pressure or cholesterol medicines, and those preventive strategies we do have such as drugs which reduce the risk of breast cancer in women at increased risk go woefully underused.


We can’t force people to go to the doctor to get screened for colorectal cancer.  If we did, we could reduce deaths in a matter of years.  We can’t force people to get screened for breast or cervical cancer. 


If we did do what we already know, we could significantly reduce the risk of cancer and deaths from cancer.  But we can’t force people to do what they don’t want to do.  Our technologies may be crude, but they are what we have.  And if we applied them, they would work.  Not perfectly, but better than where we find ourselves today.


The observation that as a nation we don’t fund our innovative young researchers adequately is true, except that the American Cancer Society has a long standing tradition of providing research support to these young investigators at the beginning of their careers.  Many of them have gone on to develop some of the most significant cancer breakthroughs.  Our grant recipients have 42 Nobel prizes to show for our early investment in their promising careers, frequently when no one else would listen to them.


We don’t talk about cures, we talk about converting fatal cancer into a chronic disease like heart disease, diabetes and hypertension.  We don’t talk about finding every cancer early, but how we can get more people access to better care.  We don’t talk about the miracles of cancer screening, but that it offers the best option in an imperfect world.


So we will continue to hear the stories that what we do in cancer treatment and cancer research is for naught, and I will continue to write blogs explaining why I agree on some points and disagree on others.


I am not an apologist for the advances in cancer research, diagnosis and treatment—any more than I am an apologist for the “advances” in medical care in this country where 47 million people are uninsured, millions more underinsured, and many can’t get anywhere near the care they need when they need it—whether it is for the treatment of a cancer or for the treatment of their pneumonia.


But I am someone who has “been there and done that”, and I have no interest in returning to the good old days of medicine, when we had no understanding of how to prevent cancer, detect it early or treat it effectively.  Those were days when we couldn’t do anything much to save a life from cancer, or prevent it or detect it early in its course.


I am someone who looks at the data—as we did in November with the Annual Report to the Nation, or the release at the same time of research showing the decline in cancer death rates in African Americans, especially men—and believe our glass is half full, rather than half empty.


I have not always been such an optimist, but I certainly look forward to our future with more optimism now than at any time past.

Praise The Volunteers!

by Dr. Len April 23, 2009

Praise the volunteers!!! 


That certainly is a thought that is very important to the American Cancer Society during this annual celebration of National Volunteer Week.  After all, we have millions of volunteers in thousands of communities nationwide, and even some throughout the world.


Without our volunteers, the Society—as well as thousands of other schools, churches and other organizations—could not support our core mission, let alone survive.  We are fortunate to have many wonderful people throughout this nation who are devoted to our cause.  They are what makes the American Cancer Society such a special place for so many of us, volunteers and employees alike.


Volunteers often labor for hours with little recognition.  They do what they do from the goodness of their hearts and their belief in a cause.   They offer their time and their skills because they want to make a difference, help someone who needs help, offer comfort to others in their time of need.


It so happens that this year’s National Volunteer Week coincides with another anniversary that that the American Cancer Society is celebrating: our 25th anniversary of Relay for Life. 


Within that celebration is perhaps one of the ultimate stories about how one volunteer can make a difference, and how one person with an idea can impact the lives of millions for years to come—both cancer survivors and those whose volunteer their time and skill to support those survivors and the mission of the American Cancer Society.


The story is one that is well known to many of us active in the Society, but perhaps not as well known outside the organization.


Dr. Gordy Klatt is a colorectal surgeon in Tacoma, Washington.  25 years ago, Dr. Klatt decided that he wanted to raise money for the American Cancer Society by walking and running around a track for 24 hours.


25 years later, Dr. Klatt’s idea has endured as the American Cancer Society’s Relay for Life, arguably one of the most successful volunteer efforts in the world. 


Here are the numbers:


  • Since that first event in 1985, Relay has raised approximately $3 billion, making it the largest global fundraising event of its kind.


  • Since 1985, more than 45,000 Relay events have been held in the United States.


  • In 1996, Relay For Life expanded beyond the United States’ borders, and it now takes place in 19 other countries, including Australia, Brazil, Canada, Denmark, France, Germany, Guatemala, Honduras, Jamaica, Japan, Luxembourg, Malaysia, the Netherlands, New Zealand, the Philippines, Portugal, South Africa, Taiwan, and the United Kingdom. In many countries, Relay has helped open the dialogue about cancer.


  • In 2008, Relay For Life raised $409 million for the fight against cancer. Those funds support the American Cancer Society’s mission to save lives by helping people stay well, helping people get well, by finding cures, and by fighting back.


  • Nearly 5,000 community Relay For Life events took place in 2008. The largest Relay For Life takes place in Gwinnett County, Ga., a suburb of Atlanta.


  • More than 3.5 million people took part in Relay events in 2008 – that means 1 in every 100 Americans is a Relay participant.


  • In 2008, more than 500,000 cancer survivors took part in Relay For Life.


  • A total of 432 college campus events were held in 2008. These events raised $19.8 million.


  • Nearly 2.6 million people have visited RelayForLife.org to learn more about the event, sign up as part of a Relay team, and share information with other Relay participants worldwide.


  • In 2005, Relay For Life entered the interactive online community Second Life, and in 2008, the event raised a record-$215,000, while engaging with people around the world who otherwise might not have participated in a Relay event.


Those are, my friends, some amazing numbers.  And it is all the result of people like you who take the time to volunteer on behalf of the Society, and make it happen.


There are stories like this throughout the nation.  We all know volunteer organizations like the American Cancer Society, the American Red Cross, Habitat for Humanity and so many other worthy causes.  We all know our churches and our schools, our homeless shelter programs, our efforts to feed the hungry, to care for the homebound and elderly, to provide shelter for animals, to provide safety from domestic violence.  And there are so many more volunteer efforts that we don’t know about, yet go about their business every day, doing good helping others.


All of us can take pride in what we do for our communities and our neighbors through volunteering.  Not all of us will see our ideas grow like Dr. Klatt.  But every one of us has within us the power to touch the soul of another, perhaps directly, perhaps from afar.


Despite our troubles these days, each of us in a way is very blessed to live in a land of relative plenty.  To be able to give back—even in a time of our own personal need—is perhaps one of the noblest goals of all.


To all of our American Cancer Society volunteers, and to all of you who volunteer in whatever way you choose, from our hearts to yours, thank you for everything that you do every day.  We are all blessed for your efforts.

Filed Under:

Cancer Care

The Special Meaning Of "Happy Birthday!"

by Dr. Len April 21, 2009

“Happy birthday to you, happy birthday to you…”


How many times a year do you sing the birthday song or wish a loved-one, a friend, a colleague or anyone you know happy birthday?   Although sometimes done casually and without much thought (except for those of us over the mystical age of 39), there actually is a lot of meaning in that greeting, more than we frequently acknowledge.


For many of us, especially cancer survivors, that greeting is more than a casual gesture to wish us well.  It marks survival, progress and the hope of birthdays to come. 


To acknowledge and celebrate those birthdays, the American Cancer Society announced today the launch of a nationwide campaign as “The Official Sponsor of Birthdays”. (You can get more information at www.morebirthdays.com).


We know that hundreds of thousands of lives that would have been lost to cancer and its consequences have been saved over the past two decades.  We know that those lives have influenced many other lives, and as a result there are an untold number of people in this country and throughout the world who are indeed celebrating birthdays that otherwise would not have occurred.


In my mind, that is a pretty remarkable accomplishment.


When I talk about the strides we have made against cancer, I frequently mention the “leverage of survivorship”. 


“Leverage” is a word that doesn’t have a particularly good meaning these days.  But when we talk about the “leverage” of saving a life, we talk about the impact of that person on many others, including loved ones, friends, colleagues, the work people do, the lives they influence, the good they bring to this world.  Save one life, and you impact so many others.  That’s the type of leverage we can appreciate.


When it comes to cancer, imagine our “leverage” in 2009:


In the early 1970’s, there were 3 million survivors.  Today, according to the National Cancer Institute, there are over 12 million.  Picture the number of birthdays that are being celebrated this year that never would have happened if we hadn’t made progress in preventing, detecting and treating cancer. 


That, my friends, is a lot of leverage.  That is also a lot of birthdays.


Our reality today is special: perhaps the life of a person saved, or the blessing of never having to hear the words “you have cancer”, since we now have the means to prevent some cancers as well as detect others early in their course.  With our successes there are also difficulties: unexpected near and long term side effects from treatment, emotional problems and financial issues clearly influence the quality of life of cancer survivors.


However, that I don’t think there are many cancer survivors who would consider having more birthdays a problem.  It is something to celebrate in every sense of the word.


The birthday campaign also gives us the opportunity to highlight what we do at the American Cancer Society, which is saving lives by helping people stay well through taking steps to prevent cancer or detect it early; helping people get well by guiding them through every step of the cancer experience; by finding cures through funding and conducting groundbreaking research; and by fighting back by encouraging lawmakers to do their part to defeat cancer and by rallying communities to join the fight.


To be sure, all of us know birthdays that will not be celebrated this year or ever again except in our special memories.  We must acknowledge that no matter the progress we have made, there is still much to learn and many to save. 


Which gives us even more reason to reflect for just a moment on what it really means to wish someone “Happy Birthday!” 


As you think back on the special moments we have all shared on our birthdays, take that thought and join the American Cancer Society in it efforts to help everyone celebrate many, many more happy birthdays for years to come--even if you plan on remaining 39 years old forever.



Is Comparative Effectiveness The Answer?

by Dr. Len April 17, 2009

There are two new buzz words that could have significant implications for our health care going forward.  Those words are “comparative effectiveness.”


Why is comparative effectiveness so important?  Because depending on your interpretation and definition of the concept, this could be anything from a very much needed way to address some nagging questions about how we treat different diseases or the forerunner of a more aggressive effort to control medical costs.


It is no secret that many of us think we spend too much money on health care.  We have a difficult time in this country demonstrating that we get true value for the money we spend.  Our technology in health care is state-of-the-art, unlike any place else on earth.  However, our outcomes are far down the list when we compare ourselves to other countries when we look at some measures of health, such as our average life expectancy.


One of the things we have learned over the past couple of decades is that we don’t know as much about the effectiveness of our treatments as we should. 


For example, are newer medicines for the treatment of common chronic diseases like diabetes and high blood pressure really better than the older drugs that are substantially less expensive?  In cancer, the question would be whether drugs that doctors use in treating patients—especially at the end of life with third or fourth line therapy for metastatic disease— are really appropriate if there is no evidence that they provide significant benefit under such circumstances?


Just look back on our experience with hormone replacement therapy, which took years to develop a sufficient body of evidence to help us understand the true benefits and risks of these commonly used medicines.


I could go on, but in my world comparative effectiveness means trying to get to the heart of these issues.  There simply has been very little money available to organize the type of research that needs to be done to answer these fundamental questions.  It would be—in my opinion—a good thing to be able to conduct such studies and get the evidence we need.


But there is another side to the comparative effectiveness debate that is beginning to raise some concerns, especially in the context of health care reform.


I have personally been troubled about how easily some think we can easily reduce health care costs in the United States. 


I have been around for a while, and if someone had the answer to that question (think managed care and Medicare, the former which is supposed to organize networks of care and the latter for the most part intent on driving down payments to the lowest fee) I think we would have seen it already.  We haven’t, and we aren’t going to get there quickly with our current “piece work” payment system.


Enter comparative effectiveness definition #2: we should carefully study the evidence supporting our treatments, and if we don’t have evidence, we shouldn’t pay for the treatment.


In cancer, it goes to the question of off-label therapy which I addressed in a recent blog discussing articles that appeared in the Annals of Internal Medicine.  No evidence, no treatment was the conclusion of the journal’s articles and editorial.  The problem is that the majority of cancer treatments in this country are in fact off-label based on the opinions of experts who have reviewed the evidence, none of which may be sufficient for a company to go to the FDA and get approval for a specific cancer drug or combination of drugs to treat a specific cancer.


Another example might be CT colonography.  The American Cancer Society thinks the evidence is sufficient to recommend this test as a reasonable one to prevent colorectal cancer.  The US Preventive Services Task Force does not.  The Centers for Medicare and Medicaid Services (CMS)—which administers the Medicare program—has issued a preliminary decision not to cover the test.  Their final recommendation is currently under review.  And this is a test where there is published literature to support its value and its use.


On the other hand, when I sat on a panel to evaluate the evidence supporting the use of PET scans in cancer, the quality and amount of credible information to support PET scanning in the diagnosis and treatment of cancer was actually very limited.  It was only because we had data from a PET scan registry that had followed some patients on Medicare that we got anywhere near concluding that the science in any way supported the use of PET scans.  And this is for a test that is used routinely and accepted without question by cancer specialists in the United States.


In a comparative effectiveness world as envisioned by some, they would use this process to deny payment for “unapproved” treatments under government programs.  That, to me, is not comparative effectiveness.  It may be something else, but it isn’t comparative effectiveness.


 In the United Kingdom, they have a group called NICE that determines what medical services are paid for by the National Health Service.  I have been interviewed fairly often on the topic of how cancer treatment differs in the United States and Britain, and how our systems differ in advancing new technologies.  Inevitably, the questions come down to which approach to providing health care is best: basically open access to everything, or strict limits which allow more people to be covered?


I am not a fan of the concept that every new test, every new drug and every new gadget necessarily improves our health care here in the United States.  But there have been some major examples where a new treatment is available quickly here, such as the use of Herceptin as an adjuvant therapy in HER-2 positive breast cancer, long before Britain decides that  they can pay for it.


My concern is that if we adopt a “strict evidence” standard here in the United States, we are going to become much more like Britain.  Maybe that’s a good thing, maybe it’s not.  I can’t make that determination.   That’s something that needs to be discussed and debated.  But it has to be an open and honest discussion, not couched in words that have different meanings to different people.


We can’t go on spending the way we have on health care, without expecting some limits of some kind.  We simply can’t afford it as a nation, while millions go without insurance and adequate medical care.  We are going to have to make some decisions at some point on how we can more effectively make our system more rational.  Right care for the right person at the right time is a responsibility for all of us, doctors, medical professionals, patients and families alike.


How we address the question of “comparative effectiveness” and what it means and what it is expected to accomplish may seem like a small point that is flying under almost everyone’s radar as we tackle larger issues, but I suspect if we don’t get it right we will live with the consequences for years to come.



Filed Under:

Cancer Care | Medicare | Treatment

Vaccine To Treat Prostate Cancer:Are We There Yet?

by Dr. Len April 14, 2009

Another day, another announcement of a potentially promising new cancer treatment, and another day of caution. Dendreon is the name of the company that issued the press release and has worked for years to develop the vaccine to treat advanced, hormone-refractory prostate cancer. 


In today’s announcement, the company said that the vaccine—called Provenge--“met its primary endpoint of improving overall survival compared to a placebo control.  The magnitude of the survival difference observed in the intent to treat population resulted in the study successfully achieving the pre-specified level of statistical significance defined in the study’s design.  The safety profile of Provenge appeared to be consistent with prior trials.”


But not everyone is ready—just yet—to say the battle is won.  And the advocacy community is poised and ready to fight back if anyone suggests we not accept today’s announcement as the final word as to whether or not this vaccine is effective.


Take for example the comments from the American Cancer Society’s chief medical officer, Dr. Otis Brawley, posted on-line today at Forbes.com:


“It certainly sounds good, but we really need to see the details…I will be watching with interest and some hope…Surprisingly, some companies often lack the expertise to fully analyze these trials appropriately,” (Brawley) says.


Within minutes after the story was posted, we started to receive emails criticizing our “wait and see” approach to the news.  And we weren’t alone.  Posts on the Forbes website claimed the author of the article was inappropriately downplaying the results of the study as well.  The suggested “payback”?  The author should get prostate cancer and be denied Provenge as a treatment.


The announcement from Dendreon is certainly hopeful news for the men in this country who have advanced prostate cancer.  However, until the data is carefully reviewed we won’t know for certain how successful the drug really was in producing a meaningful response in what to date has been a very difficult cancer to treat when it spreads through the body.


This is a vaccine that has travelled a long and difficult road to get to today’s announcement.  Provenge has sparked controversy in the past and has been the focus of ire from some in the prostate community who have railed against the FDA and others for not approving or supporting the vaccine despite the absence of clear evidence that the vaccine was effective.


Advanced prostate cancer is truly a disease in need of a treatment breakthrough.  The American Cancer Society expected in 2008 that about 186,000 men would be diagnosed with prostate cancer, and 28,660 men would die from the disease (data for 2009 projections is still not available).  The good news is that the frequency of new cases and deaths from prostate cancer have been declining in this country.


But for men who either diagnosed after the disease has spread, or who recur after primary treatment with surgery or radiation therapy, the outlook is grim.  Hormonal manipulation usually works for a period of time, but is not without side effects that negatively impact the quality of life.  And for men who have more aggressive disease that escapes from the hormone treatments, there is little to offer in terms of truly effective chemotherapy.  Advanced prostate cancer can linger for a long time, and frequently causes severe symptoms with pain being a frequent and severe problem.


So any new treatment that might improve survival and quality of life for men with advanced prostate cancer would be truly welcomed.


There is another wrinkle to this story that is equally important, and that is the fact that if this vaccine is successful, it will be the first time a vaccine has shown any lasting, confirmed benefit in the treatment of cancer.  Truly, in a sense, this could be the answer to a search that has dogged and defeated cancer researchers literally for decades as they have tried to manipulate our bodies’ own immune systems to help defeat cancer.


We won’t have any real information to look at until the data from the clinical trial is presented at a national urology conference on April 28.  Certainly many eyes and ears will be focused on that presentation, not the least of which will be members of the investment community.  Even then, the presentation will offer only a snapshot into the effectiveness of Provenge.


As I write this, we don’t know exactly what the data will show.  The company is prohibited from releasing that information to anyone prior to the presentation. But we do have a glimpse as to what we might expect, based on a conference call the company held with investment analysts earlier today.


Here is a snapshot of the call:


First, the company would go no further with the details of the data except for what they put in the press release.  They did mention that their report today was “top line” and that further analysis of the trial information was necessary.


The CEO of the company, Dr. Mitchell Gold, went on to say that the results of the trial were “unambiguous”, and that the trial clearly hit is target endpoint.  When pressed to define that endpoint, Dr. Gold declined to provide more information, citing the need to hold back any further comments pending the presentation in two weeks. 


Dr. Gold also mentioned that the median survival in the trial was consistent with other studies of Provenge, and that the vaccine clearly prolonged the overall survival of the patients who either received the vaccine or were supposed to receive the vaccine (called an “intention to treat” analysis, which is appropriate).  He also mentioned that some patients who were in the placebo group did cross-over at a later date to receive another formulation of the vaccine.  These patients remained in the placebo group as part of the analysis reported today, which means it was even more difficult for a difference to be noted in favor of the vaccine in the treated group if the vaccine had any positive benefit.


Dr. Gold emphasized repeatedly during the call that the analysis was only “top line” and that the company has not had a lot of time to examine the data.  Nonetheless, in response to several questions, he indicated that the company is planning on resubmitting an approval application to the FDA in the latter part of 2009, and is already examining ways to initiate marketing and manufacturing for Provenge.


There were several comments during the call stating that the results of the current trial support improved survival for men with advanced prostate cancer who received the vaccine as seen in prior Provenge phase III clinical trials of the vaccine.


The company is clearly enthusiastic about the results.  Those of us without access to the information still don’t have as clear a picture as we would like, and we look forward to the actual presentation in late April.


In a phase III trial reported in the Journal of Clinical Oncology in July 2006, researchers reported a 4.5 month increase in median survival (25.9 months for men treated with the vaccine, compared to 21.4 months for men who received a placebo instead).  However, in that same study, the vaccine did not improve the time-to-progression for men who received the vaccine (11.7 weeks for vaccine vs. 10 weeks for placebo).


For whatever reason, in that particular trial, it appeared that the vaccine had little effect on one important measure (time to progression)—which actually occurred fairly quickly in a matter of about 3 months—compared to the survival advantage, which took almost 2 years to become evident.


I don’t know if the current trial measured quality of life for the men who received the vaccine, but given the fact that advanced prostate cancer frequently attacks the bone and can cause significant pain, I hope that the vaccine—if in fact it is shown to be truly effective—can do something to control the symptoms of advanced prostate cancer.  Simply stated, if the disease progresses quickly with or without the vaccine, living an extra 4 months in agony may be worthwhile to some men, but may not be worthwhile to others.


So, the bottom line is that we anxiously await the presentation of the data and a more detailed review which will hopefully follow in the near future. 


We hope the response to the vaccine is a meaningful one, in terms of days of life and the quality of life.  And we hope that this vaccine will in fact demonstrate once and for all that we are in fact able to effectively use a vaccine to “wake up” our bodies own natural defense mechanisms to treat a notoriously difficult disease.


If this vaccine does meet those goals, this will be a major step forward on several fronts.  Unfortunately, we have learned time and again that however glowing the press reports, until “the data is in”, we won’t know for sure.


Here’s hoping….


The MRI Dilemma: Is It A Better Screening Tool?

by Dr. Len April 10, 2009

We are voracious consumers of technology in this country when it comes to our health care.  A recent discussion with a physician I know well about breast cancer screening using MRI highlights how sometimes our love-affair with technology can lead to personal dilemmas that are not easy to resolve.


The situation confronting this doctor and her patient was a fairly straightforward one: a woman in her 40’s who had dense breasts on a routine screening mammogram with no suspicious lesions, no family history and no other risk factors for breast cancer was advised in a report from a radiologist that she needed an MRI scan of her breasts.  The woman had a high deductible health insurance policy, which meant that she would have to pay several thousand dollars out of pocket to have the test done.  Simply put, she didn’t have the money readily available, but would figure out a way to get the scan if she needed to have it.


Worried that she would be forgoing recommended care, the patient had a discussion with her physician.  Given the fact that a formal recommendation had been made by the radiologist in a written report, the doctor was put in the unenviable situation of risking countermanding a colleague if she didn’t support the recommendation.  What should she do, and were there any alternatives to the recommendation for the MRI?


MRI is a very valuable tool when used appropriately.  It has substantially improved our ability to look inside the human body in search of disease.  But just because it is an advanced technology doesn’t make it right—in its current form—for every part of the body.  Breast imaging happens to be one of those situations.


In March 2007, the American Cancer Society released its recommendations for the use of MRI in screening women for breast cancer.  In short, women who have a high lifetime risk of breast cancer are indeed candidates for screening with MRI along with mammography.  But women at average risk do not fit the recommended category for this expensive test.


Women with dense breasts on routine mammograms, however, do have an increased risk of breast cancer.  But the evidence that MRI is helpful is limited at best.


This is what the authors of the guideline had to say about the use of MRI in screening women with dense breasts on mammogram:


“Although there have been several trials reported looking at the accuracy and positive predictive value of MRI and mammography in women with high breast density, all of these trials have been conducted in women with known or highly-suspected malignancies within the breast. To this point, there has been no Phase III randomized trial reported that has shown a reduction in either mortality or in the size of diagnosed breast cancer when comparing breast MRI with mammography in women with high mammographic density.”


The problem, it turns out, is that MRI can find lesions in the breast but it isn’t particularly specific at finding actual breast cancers as compared to benign lesions.  As a result, there are a larger number of false positive results with breast MRI compared to routine screening mammograms. (A false positive is when the doctor sees something on the scan that looks like a breast cancer, but turns out to be a benign lesion.) When you have a high rate of false positives, that in turn means that more women will have more biopsies for lesions that turn out not to be breast cancer.


Because of this, studies have shown that the women who benefit most from screening for breast cancer with MRI are clearly those who have a significantly higher lifetime risk of getting breast cancer, such as those with the BRCA 1 and BRCA 2 genetic mutations.


The other wrinkle to this problem is that MRIs of the breast should be done by radiologists who do a lot of these studies, and have the equipment to do a biopsy guided by the MRI if there is a suspicious lesion found on the study.


Again, from the ACS guideline on the use of MRI in screening for breast cancer:


“Recommendations are conditional on an acceptable level of quality of MRI screening, which should be performed by experienced providers in facilities that provide MRI-guided biopsy for the follow up of any suspicious results.”


As I travel around the country that I am hearing from more primary care physicians that they are being confronted with the same question as my doctor friend described in the opening of this blog.  More and more women are being told by their radiologists that they need an MRI because they have increased breast density, so this does not appear to be an isolated question.


So here we are, with the medical technology “arms race” heating up on another front.


A center that does breast MRI has to do a fair number of these studies in order to become and remain proficient in the technique.  Few radiologists want to be left behind when it comes to offering a new service that patients want and expect to be available, even in small rural towns.  And the public demand and expectation has been increasing in parallel with more publicity about breast MRI.


This doesn’t mean that doctors are necessarily making inappropriate recommendations for breast MRIs to increase the number of studies they do or to pay for the special equipment they have to buy to do these studies.  But it does raise the question whether all of these new recommendations to get a screening breast MRI are in fact improving the quality of our health care and reducing deaths from breast cancer.  According to the American Cancer Society, we can’t say with any certainty that MRI actually reduces deaths from breast cancer in women with dense breasts.


Add to this discussion the fact that any primary care physician or gynecologist who ignores a radiologist’s recommendation for a breast MRI or advises a patient that they may not benefit from the study could find themselves on the wrong end of a lawsuit if their patient should be the one to develop a breast cancer at a later date.


We are facing more and more of these dilemmas when it comes to how we use our technology.  We don’t always have the science to back up our practice.  We rely to a considerable degree on the “art of medicine”, and in the process we spend gobs and gobs of money on technologies where we don’t have a clear path to tell us that it really makes a difference that we can afford.  If we do something often enough and say it often enough, we begin to believe that it works—even if there is no evidence to support that conclusion.


So what does my doctor friend and her patient do?  They have discussions and they make decisions and they hope that the decisions they make are the right ones for them.  And they get the biopsies and suffer the trauma and inconvenience that will inevitably result, since breast MRI is not as perfect as some would have you believe.


And we go on and on and on and on. 


The demand for health care is endless.  Unfortunately, the resources to pay for it are not.  And I’m not certain that even if the resources were available, we would necessarily be better off.


Sooner or later, we are going to have to come back down to the planet earth and realize that we are not getting the value we should be expecting for our health care dollar.  And then we will have to find a way to balance all of this technology against what it costs and the benefit it delivers.


I suspect that day is going to come sooner rather than later.  If we don’t do this in some systematic and rational way, it will be forced upon us in a manner that many of us are not prepared for. 


“If we build it, they will come” may make a good movie story, but it is lousy way to deliver health care.

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.