The positive news continues: cancer death rates have continued to fall in the United States, for men and women, maintaining a trend that began in the early 1990's. That's the essence of a report released today by the American Cancer Society, the National Cancer Institute, the Centers for Disease Control and Prevention and the North American Association of Central Cancer Registries in the Journal of the National Cancer Institute.

The report, titled in part "Annual Report to the Nation on the Status of Cancer, 1975-2009" also features a special section on the burden and trends in Human Papilloma virus (HPV) associated cancers and HPV vaccination coverage levels. Unlike the continuing decline in cancer deaths in the United States, we could be doing a much better job of getting young folks vaccinated against HPV and reducing the incidence and death rates from several HPV-associated cancers, according to the authors of the report and an editorial that accompanied the report.

This report comes out every year. It is a summation of what we know about the trends in incidence rates for the most common cancers in the United States among both men and women as well as the trends in death rates from those cancers that lead to the highest mortality in the general population as well as specific ethnic groups. It is in a real sense a report card on our progress, which in large part is good but in a number of cancers, not so good.

The good news is what we have come to expect: since the year 2000, the overall cancer death rates have continued to decline 1.8% per year in men, 1.4% in women and 0.6% per year in children. That may not sound like much, but when you consider the fact that this is an average change seen every year, those numbers begin to add up. More...

Every year at this time cancer specialists and researchers from around the world descend on Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO) to hear the latest breakthroughs in cancer research and treatment.

Through all the fog of all the information--which is impossible for any one individual to evaluate much less comprehend--there is always the search for the "buzz," or the next "big thing" that will make a huge impact on cancer treatment and the lives of the patients we care for and the people we love who are affected by cancer.

This year, it is apparent already that one of this year's "big things" are the reports of new success in an old and ongoing effort to harness the body's own defense mechanisms to fight cancer. And--being the skeptic that I can be at times--I will throw my hat in the ring that maybe this is going to be one of those events that truly will impact cancer care. But despite the enthusiasm, we must always temper our expectations with reality and lessons we have learned from the past that early success doesn't always tell us the whole story.

Without going into great detail here, the reality is that in early stage trials an antibody drug now called "BMS-936558" produced significant responses in a number of patients who had certain advanced cancers and had failed multiple prior treatments. In these studies, patients with melanoma, kidney cancer and non-small cell lung cancer showed responses to this new drug and some of those responses lasted for over a year.

When you see these kinds of results in cancers that are ordinarily difficult to treat, and in patients who have failed multiple other therapies, that becomes news. More...

There are few times in life when one gets to watch history being made. Today is one of those times.

I am in New York with a number of colleagues from the American Cancer Society and other committed organizations to observe a UN High Level Meeting which will--at long last--put non-communicable diseases on the international agenda. The impact of the decisions made here over the next two days can indeed change the face of global health forever. More...

I don't often write blogs about articles that appear in newspapers, but in this case I am going to make an exception for today's excellent front page story in the Wall Street Journal by Ron Winslow discussing the coming of age of genetics and genomics in diagnosing, treating and predicting the behavior of the disease we now know as cancer.

But even though Mr. Winslow may have pre-empted the thought that for me the seminal theme of this year's annual ASCO meeting in Chicago was related to the impact of genetics on cancer research and treatment, his well-written "scoop" won't prevent me from weighing in with my opinion that this year represents another one of those seldom moments when we reach a tipping point in cancer research and the application of that research to the diagnosis and treatment of cancer.

It was obvious literally from very beginning of the meeting when Dr. George Sledge--the President of ASCO--addressed thousands of cancer professionals from around the world and talked about the impact of the forthcoming era of personalized medicine.

In the past, we have had the chemotherapy era, where we were able to put combinations of toxic drugs together to cure and control some forms of cancer.  We have had the adjuvant era, when we learned that using chemotherapy could delay the progression of cancer after primary treatment, usually surgery.  We have most recently had the targeted therapy era, when we learned that drugs targeted at genetic changes in cancer cells could impact survival, sometimes substantially.  We wish we had a vaccine era, although there have been some practical successes and hopeful research that continues in that arena.

And now we have the genomic era. More...

Today’s announcement by the Food and Drug Administration (FDA) that they approved Provenge® for the treatment of advanced, hormone resistant prostate cancer is significant for several reasons, not the least of which that it offers new hope to men with advanced prostate cancer where progress in treatment has been very slow in coming.

Equally important, it closes the door on decades of unfulfilled hopes that tumor vaccines and immunotherapy would eventually play a significant role in cancer treatment.  We now have a demonstrated success, which is especially important given the many near-misses that have occurred over the years.  This reinforces for many the dream that one day we would be able turn on the body’s own defense mechanisms as one more approach to treat (or one day—perhaps—prevent) certain cancers.

More...

An article in today’s New England Journal of Medicine reports some interesting and intriguing research that may help some women with a not uncommon pre-cancerous lesion of the vulva called vulvar intraepithelial neoplasia, or VIN.

By using proteins found in the cancer-causing human papilloma virus type 16 (HPV-16), the researchers were able to make a vaccine that actually led to an effective treatment for a small group of women with VIN, resulting in complete disappearance of the lesion in almost half of the women they treated.

You may have heard of HPV infections.  These are the viruses that cause cervical cancer.  Two of these viruses—types 16 and 18—are responsible for the majority of cervical cancers in the United States.  They are also the viruses targeted by currently available vaccines which prevent infection with HPV thus reducing the risk of developing cervical cancer.

It turns out that the same viruses are also related to VIN, especially type 16 which causes over 75% of VIN. (VIN is a superficial lesion on the vulva which can actually last for many years.) 

The problem is that the treatments for VIN are sometimes unsatisfactory, and the lesions can recur frequently after treatment.  Topical medicines, surgery and laser treatments are commonly used.  More recently, an antiviral medicine called imiquimod has been reported to be effective and less irritating.  About 1 out of 65 VIN lesions can resolve spontaneously.

And, just like what can happen in the cervix where the HPV infection progresses on to cervical cancer, untreated VIN can become an actual vulvar cancer.  Fortunately, this is uncommon.

In this current report, the doctors made a vaccine using cancer-causing proteins from the virus.  They treated women with advanced pre-cancerous VIN by giving them the vaccine under the skin of the arm or leg every three weeks for a total of three to four injections.  Side effects were tolerable, and frequently included a local reaction at the vaccination site in addition to flu like symptoms, chills and tiredness.

The responses in some of the women were remarkable: At one year, 6 of the 19 patients had a partial response to the vaccine. 9 of the patients (47%) had complete disappearance of the VIN, which lasted for at least another 12 months.  As a result, 79% of the women responded to the vaccine.  This compares to a complete response rate of 35% for lesions treated with imiquimod, according to the report.

Unfortunately, not all of the women had such positive responses to the vaccine.  Two of the participants went on to develop cancer, and one of those women had shown a previous partial response to the vaccine.

The researchers also measured whether the women’s immune systems responded to the vaccine.  All of the women in the study did have a response, and those with a complete resolution of their VIN at 3 months after treatment had much stronger responses compared to women who did not have a complete regression.

What’s interesting to me about this research is that it seems to work in a way that is different from what we have seen before.

We are all familiar with the typical types of vaccines, where the vaccine contains a protein from a virus or bacteria that is given to us when we aren’t sick with an infection and then prevents us from getting the same infection at a later date.

Here we have a situation where the woman is already infected with the virus, and her body has either not developed a response to the infection or become “tolerant” to the virus.  That’s usually a situation where vaccination doesn’t work.  Think of having the flu, then getting the flu vaccine.  Basically, it’s too late. 

That same theory carries over to the currently available cervical cancer vaccine.  If a woman has already become sexually active and infected with HPV, then giving her the preventive vaccine isn’t going to be effective in reducing her risk of cervical cancer.

But, for some reason, in this trial giving a piece of the virus to stimulate the immune system after the infection had set in did work. What I don’t understand is how that happened.  It just is not what one would ordinarily expect based on the science.

These doctors weren’t interested in making a prevention vaccine.  What they developed, as they report, was a therapeutic vaccine.

Maybe I shouldn’t be so worried about how this happened, and just be glad that in fact it did happen. 

The implications of this research are significant. 

First, it may mean that this vaccine will be studied further (this was a very small, early stage trial) and eventually be available for wider use in the treatment of women with VIN.

But—perhaps more importantly—it raises the question of whether a similar approach could be used in women who have advanced pre-cancerous lesions in the cervix.

These researchers have actually previously reported studies using the same vaccine in women with either advanced or treated cervical cancer.  In one study, they vaccinated women who had cervical cancer that was successfully treated surgically, and were able to induce an immune response to HPV-16 using this vaccine. 

As they stated in that article, the results of the study “indicates the potential of this vaccine for the immunotherapy of HPV 16-induced progressive infections, lesions, and malignancies.”

In plain language, if this vaccine is effective in VIN, and it can demonstrate the ability to cause an immune response in women who have already been diagnosed with cervical cancer, then maybe it can also be effective in treating women who have pre-cancerous cervical lesions as well.

I suspect it will be some time before we know the rest of the story as to whether this vaccine is truly effective in treating women with VIN or whether it can improve the treatment for women with pre-cancerous lesions of the cervix.  Patience is clearly going to be part of the process.

But if this theory holds up, then this report could be the foundation of a new approach to treating some not-uncommon pre-cancerous diseases.  And that is very exciting news indeed.

Two articles and an editorial in the current issue of the Journal of the American Medical Association (JAMA) about the side effects and marketing of the cervical cancer vaccine are probably going to raise questions.  They may also fuel the fires of concerns among some groups that have raised thorny political questions about the vaccine, especially as to whether or not this vaccine should be mandatory for young girls.

The primary “scientific” report in JAMA describes the results of a post-marketing surveillance program that monitors the side effects of new vaccines. 

The study, written by researchers from the Centers for Disease Control and Prevention and the Food and Drug Administration is fairly straightforward. 

In order to monitor reports of subsequent adverse reactions, the CDC and the FDA sponsor an adverse event reporting system called the US Vaccine Adverse Event Reporting System (VAERS).  Anyone can submit a report of a suspected vaccine-related adverse event to this system, even if they are not the patient, a family member, a physician or other health care professional.  Once the vaccine has been in widespread use for a sufficient period of time, those reports can be evaluated and researchers can determine whether or not there are any unsuspected safety signals, or if certain adverse events occur more frequently than would have been anticipated based on the initial clinical trials.

More than 23 million doses of the cervical cancer vaccine had been distributed in the United States between the date it was approved in June 2006 and December 31, 2008.

During that period of time, the VAERS had received 12,424 reports of adverse events following vaccination with the HPV vaccine.  Most of the reports came from the manufacturer, but unfortunately those reports did not have patient information so they could not be verified.  Also, many of the reports included multiple adverse reactions in single patients.

The most common reactions were syncope (fainting) in 15% of the reports, followed by dizziness, nausea, headache and reactions at the injection site.

772 of the reports--or 6.2%--were considered “serious.”  These reports included 32 deaths.  There were eight reports of serious allergic reactions, nine episodes of blood clots (deep vein thrombophlebitis or DVT) 31 episodes of ascending paralysis (Guillain-Barre Syndrome, or GBS) in addition to spinal cord inflammation, pancreatitis, blood clots to the lungs, convulsions, allergic skin reactions, and autoimmune disorders.

There were 1896 reports of fainting, and 15% of those reports included a fall.  Of the people who fell, about 2/3 had a head injury as a result of the fall.

The researchers tried to verify many of the more serious events, but were stymied by the lack of medical information that was available.  In addition, a number of the reports of serious events were based on hearsay, where the person who reported the event did not have first hand knowledge of the reaction.

Obviously, the greatest concern is with the reports of 32 deaths that may have been associated with the vaccine.  Of those cases where data was available, there were several different causes of death including four that were unexplained. 

The authors conclude that the safety profile was in line with what would have been expected from the initial clinical trials of the vaccine.  They did point out, however, that there was a higher rate of syncope and blood clots (DVT) than was expected.  They also noted that surveillance is continuing.

Syncope after vaccination is not a new problem with vaccinations.  The authors note that fainting after a shot is not unusual in young people, especially young women between the ages of 11 and 18. They emphasized the need for patients, families, and health care professionals to follow recommended precautions after giving this vaccine, in order to prevent more serious injury.

The authors also noted that this reporting system is “passive.”  That means it relies on people letting the CDC and the FDA know about adverse events.  They also think publicity increased the number of adverse events that were reported since there were three times the number of reports for this vaccine compared to the rate seen for all other vaccines combined.

Their conclusion?

“The post licensure safety profile presented here is broadly consistent with safety data from pre-licensure trials.  Because VAERS data must be interpreted cautiously and cannot generally be used to infer causal associations between vaccines and (adverse events), post licensure monitoring will continue and identified signals may be evaluated using epidemiologic observational studies.”

So that’s the science.  Now for the more controversial part of this report, which calls into question how this vaccine was marketed and what role medical associations may have played into misleading their physician members about the vaccine.

The authors of this article, from the Columbia College of Physicians and Surgeons in New York, refer to “critical and unresolved questions” about the vaccine in terms of how it was marketed, whether the vaccine was being targeted to those young women who need it most, and whether the medical societies were really unbiased in their presentations about the vaccine.

The authors maintain that by marketing this vaccine to prevent cervical cancer as opposed to preventing infection with a virus resulted in the vaccine gaining greater acceptance in the community and among physicians.  The authors claim that the public was led to believe that every young girl was at equal risk of getting cervical cancer, as opposed to focusing on young girls at greater risk of getting cervical cancer.  Those girls at risk are frequently economically and educationally disadvantaged which results in a lower likelihood that they will follow cervical cancer screening recommendations as they grow into adulthood.

To me, the most disconcerting allegations in this article are leveled at “professional medical associations” (PMAs) which are physician membership organizations that are highly regarded and have a significant nationwide presence.  The authors suggest that some of these organizations altered their professional focus and messaging surrounding cervical cancer as a result of corporate funding.  They established well-resourced speaker bureaus funded by the manufacturer to provide continuing medical education lectures, including carefully designed scripts and slides.  Even potentially controversial or difficult questions had very specific responses crafted as part of these kits. 

The authors conclude:

“As marketing of this HPV vaccine demonstrates, pharmaceutical company campaigns can undercut the most cost-effective and appropriate use of new agents to the detriment of adolescent health.  By making this vaccine’s target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to all adolescents maximized, and the subpopulations most at risk practically ignored…Under no circumstances should PMAs administer product-specific speakers’ bureaus, nor should they accept funding that requires them to report activity to the donor.”

These are serious comments. And don’t forget that they appear in JAMA, which is the medical journal published by the American Medical Association, the granddaddy of professional medical associations (although there is no suggestion that the AMA was engaged in any of these activities).

The editorial also discusses the complexity of decision making when it comes to evaluating the risks and benefits of a new medical treatment, such as the cervical cancer vaccine.  The writer points out persistent lack of knowledge about the vaccine, such as the impact on cervical cancer rates 20 or 40 years from now, and the fact that more long term studies about the vaccine were needed but have not yet been reported.

The opinion of the editorialist is bound to be the topic of discussion in the medical community:

“The net benefit of the HPV vaccine to a woman is uncertain.  Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened.  So rationally she should be willing to accept only a small risk of harmful effects from the vaccine. 

“When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit.  Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed.  The balance will also tilt if the adverse events are not calculated correctly.”

So what does the American Cancer Society recommend? 

Our guidelines call for routine vaccination of girls ages 11 and 12, and as young as 9.  We also recommend the vaccine for women ages 13 through 18 to “catch up” missed vaccines or to complete the series of three shots.  We do not believe there is sufficient evidence to recommend for or against routinely vaccinating women between the ages of 19 and 26, and those women should have an informed discussion with their health care professional about the benefits and risks of the vaccine.

All of this discussion led me to go back to our original guidelines publication.  We make every effort to have the best experts participate in our guidelines panels.  We do not take funding from industry to support our guidelines efforts, and we do not gain financially from producing our guidelines.  I do know that our panel spent countless hours reviewing the evidence, and discussing and debating many aspects of the HPV vaccine before they made their recommendations.

That said, I would be remiss if I didn’t note that a number of the experts on the panel do in fact have industry relationships related to the cervical cancer vaccine.  These are, after all, the experts that everyone seeks for their opinions.  I know many of them personally and by reputation, and all are highly regarded.  But as I noted in last week’s blog on whether or not physicians routinely recommend the vaccine, there are situations where I feel obligated to note potential conflicts, and this is one of those situations.

Ultimately, you will have to make your own decisions and conclusions about what all of this means—especially if you have a daughter who is eligible to receive the vaccine.  Far be it from me to tell you what to do, but I do continue to support our guideline recommendation. 

There is nothing in these articles that would make me change my mind.  Controversy is one thing, but good medicine is another.  And many experts I know and trust believe this vaccine continues to be “good medicine.”

The headline on the press release says, “More Than Half of Texas Physicians Do Not Always Recommend HPV Vaccine to Girls.”  That sounds bad. 

The “sub headline” in the press release says, “Approximately 50 percent do not recommend the vaccine.”   That sounds really bad.

The problem is that the headline is misleading and the “sub headline” isn’t true.

When you read the actual research paper, you find out that 75-87% of the doctors are making the right recommendation most of the time. 

Given the strong social and political interest in this topic, those differences have significant implications, especially given the headline and sound bite world we live in today.  And that could influence how this paper may be used to drive public policy.

First, a bit of background:

We know that the majority of cervical cancers in the United States are caused by two types of human papilloma virus, or HPV. 

A cervical cancer vaccine was introduced in the United States in 2006 which could significantly reduce the risk of cervical cancer from these viruses.  We also know that the vaccine has not been used as often as was predicted, with somewhere between  6% and 25% of 11 to 18 year old girls in this country having been vaccinated to date.  We also know that routine vaccination is recommended for 11-12 year old girls by several reputable organizations and federal panels. 

The reason for the young age is that the vaccine is not effective once a girl becomes sexually active.  Additional recommendations, including those from the American Cancer Society, include offering the vaccine for girls as early as 9 years old, and as a “catch-up” for girls ages 13-18.  The Society also recommends a discussion between a woman and her health care professional about cervical cancer vaccination if she is between the ages of 19-26.

The current report appears in the August issue of the journal Cancer Epidemiology Biomarkers and Prevention. 

The researchers had three primary questions they wanted to answer with their study:

First, they wanted to find out whether or not physicians were recommending cervical cancer vaccination to 11 and 12 year old girls.  Second, they wanted to know if physicians would recommend the same vaccine to 11 and 12 year old boys if it became available, understanding that studies have shown the same vaccine now used in girls will also reduce genital infections with HPV in boys.  Finally, the researchers wanted to know if physicians agreed that HPV vaccination in 11-12 year old girls should be mandatory.

The study was conducted in Texas, which has an interesting political history with regard to cervical cancer vaccination.  Briefly, after the vaccine became available, the Texas governor issued an order that the vaccine would be mandatory in 2007 for girls entering the sixth grade in Texas.  However, after strong political protests, the legislature voted to rescind that order.

The researchers conducted an email survey to answer the questions they had posed above.

Focusing on just the physician recommendations to vaccinate 11 and 12 year old girls, the study concluded, “Half of the physicians in this study did not follow current recommendations for universal HPV vaccination of 11-to-12 year-old girls.”

Doesn’t sound too good, does it?

But wait a moment.  In a graph in the paper, it says that 75.4 of the doctors “always/usually recommend vaccine to girls” in the primary target population of 11-12 years old. If you look at the same number for girls ages 13-17, the percentage actually climbs to 87.5%.

As a physician who has been in practice, and as someone who is very interested in the need to get doctors to recommend appropriate cancer screening tests to patients, that number actually sounds pretty good.  In fact, I think it would be very difficult to get much better than that, especially in the 13-17 year old category.

Essentially, the headline all depends on whether you think there is much practical difference between “always” and “usually.”  Frequently, researchers combine those categories into a single number because of the practical implications.  Indeed, in their own graphical presentation of the data, the researchers in this paper combined the data.  It’s when they wrote the conclusions that they elected to highlight that differences.

And that “sub headline” which says that approximately 50% of the physicians in Texas do not recommend the vaccine should just go away. It is a serious misstatement of the facts in the paper.

Using this information, the authors conclude that “additional efforts are needed to improve clinicians’ awareness of and adherence to national recommendations.”

The study also noted that the most effective way to get these girls vaccinated is to mandate the vaccine.  “State vaccination requirements that would ensure high uptake of HPV vaccines also have the potential to narrow existing racial, ethnic, and economic disparities in cervical cancer incidence and mortality…(More than) 40% of Texas physicians in this 2008 study supported mandatory HPV vaccination.”

The authors do point out that there are several barriers to vaccination, including costs and misperceptions of safety and effectiveness—as well as personal parental beliefs—that may impact the rate of vaccination.  But they also imply that doctors aren’t doing their job as well as they should. 

I simply don’t agree that the data on its face supports that conclusion, and I don’t agree that the data necessarily reflect the opinions and/or practices of physicians across the country.  When I dug deeper into the study, I found I had questions about how representative the sample was of all practicing physicians, not to mention questions about how many internists and gynecologists actually treat 11 to 12 year old girls in their practices.  I also thought the study was (unintentionally) biased towards younger physicians whose opinions may not reflect the larger (and older) primary care physician workforce.

Some final items:

I want to make it clear that in my opinion this vaccine is useful in preventing cervical cancer.  I have no personal opinion (nor does the American Cancer Society) as to whether or not the vaccine should be mandatory.  The Society does recommend routine vaccination of girls 11-12 years old.

As I mentioned to a reporter during an interview yesterday, I believe that readers of this blog should be aware of potential conflicts of interest when I write about particular research reports.

In this case, one of the senior authors on the paper lists the following conflicts:

She is a co-Principal investigator on an investigator-initiated grant funded by the company that currently is the sole supplier of the cervical cancer vaccine in the United States; serves as a research consultant/collaborator on a research project sponsored by that company; and sits on one of that company’s advisory boards.

I would add that the study was funded by the Texas Medical Association Foundation.  I applaud them for supporting this research, as well as their efforts to vaccinate children in areas of the state with low vaccination rates.

I could not find any indication that the company which makes the vaccine directly or indirectly supported this research, or made some type of grant which helped get the study completed.

The key “take away” message for me is that this particular study is a case example of how one can get attention by emphasizing the problem, as opposed to applauding the success.  In my personal opinion, it shows how you can tilt the impact of a scientific paper depending on the message you want to send and the headlines (and sub headlines) that you write. 

To sum it all up, whether you think this glass is half empty or half full may just depend on your point of view.

Sometime patience pays off.  And sometimes patience means you think you have come to the end of the road, only to find that someone has built an extension for the highway.

That’s the outcome from the next study, which reported that the use of a tumor vaccine in patients with a non-Hodgkin lymphoma called follicular lymphoma were found to have longer remissions after chemotherapy if they received the vaccine when compared to patients who received the same treatment but did not get the vaccine.

This research was no flash in the pan.  The basic research which led to this study was first reported in a well-known medical journal back in 1999.  Ten years later, we have a report that the use of the vaccine in a select group of patients who were able to have their disease successfully treated and remain in remission for at least six months increased the time to progression of 44.2 months, compared to 30.6 months for the patients who also achieved a complete remission for at least six months but did not receive the vaccine.  That is over a 14 month improvement.

But this was a very select group of patients.  First, they had to have a lymph node large enough to make the vaccine.  Then, they had to achieve a complete remission of their disease on chemotherapy.  Then, they had to remain in remission for at least six months before the vaccine could be started.

Each of those requirements puts in place another filter that might influence the results of the trial.  And, as the author points out, when you look at the entire patient population with this disease, and given the effectiveness of newer for this disease treatments (which became evident during the time this trial was in progress), there in fact is not that much difference in the “real world” results in survival for both groups.

The researchers concluded that the vaccine did work.  The side effects were limited, and the vaccine may be useful in treating these patients in practice.  But we are now in a different era in the treatment of this disease, so it is basically back to the drawing board to see if the vaccine still helps in the face of newer, more successful drugs for this lymphoma.  Discussions with the Food and Drug Administration for drug approval are ongoing.

In discussing the presentation, Dr. Ron Levy from Stanford University School of Medicine made the point that lymphoma cells have unique markers not common to other cells in the body.  That is what makes this cancer a disease where a vaccine may be useful.

We now have antibodies against this target, and we have therapies based on these antibodies that are successful in treating follicular lymphoma. We can use that same target to make a vaccine.

Dr. Levy went on to ask several questions in his discussion, including: Is this result a positive result?  Could there be a role for active vaccination in patients with this disease?

He noted that this was a small study with 117 vaccinated patients.  The chemotherapy was not a “popular” chemotherapy.  Not every patient achieved a complete response and others could not maintain a complete response.  There were other unanswered questions about that study that, according to Dr. Levy, could have led to unintended biases in the results.  Finally, he concurred with the same comment that I noted above, namely that these patients were the “best of the best” in terms of the opportunity for long-term remissions for their cancer after their treatment.

Will vaccination be part of standard treatment?

As noted by Dr. Levy, the world of treating follicular lymphoma has not stood still.  The use of rituxumab (Rituxan) has shown a “powerful advantage” in improving the treatment of follicular lymphoma.  In order to find out whether this current vaccine has any value in today’s treatment program to improve the outlook for patients with follicular lymphoma, a new trial would have to be done.

Dr. Levy’s conclusions: a “qualified yes” that the trial is a positive result.  But there is much more work to do.

Which brings me back to my first comment: After years and years of work, we have a success but it is a qualified one.  It demonstrates the concept, but we don’t know if it will make a real difference in the outlook of patients treated with more modern approaches to follicular lymphoma.  We still need to travel further along that extended highway.

That, my friends, is what we call a conundrum.

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.