When I started my oncology career many years ago my research focus was on the immunology and immunotherapy of cancer.  Our goal was to solve the puzzle as to why our bodies allowed cancer to develop in the first place, and what we could do to improve our own natural response to cancer cells in an effort to help treat the disease.

The basic question that we tried to answer early on in the development of the field of cancer immunotherapy was fairly simple: If cancer cells are abnormal, why don’t our bodies recognize them as such and destroy them, much like our bodies respond to infectious agents such as viruses and bacteria?

Unfortunately, our success was limited.

Now, we may actually have a tool that helps us put theory into practice, one that may enable our bodies to recognize the cancer cell as foreign, and destroy it.

A report published today in Sciencexpress, a highly regarded medical journal, describes what appears to be the first success in using genetic engineering applied to immune based therapy, resulting in significant disease responses in two patients with recurrent melanoma.

Our tools and our knowledge were primitive when I started my research, compared to what we know today. 

We used a variety of drugs such as BCG (a vaccine used to prevent tuberculosis, which also boosts the immune system and which is still in common use today to treat certain types of bladder cancer) and developed new drugs, such as interferon (which is commonly available today and used to treat a number of conditions).  We even used a drug called levamisole, which was a medicine used to deworm cattle, and which in some fairly crude studies demonstrated activity as a booster of the immune system (levamisole even enjoyed a brief moment where it was used as part of clinical trials and treatment for colorectal cancer based on some modestly successful research studies).

But the goal of making the significant and durable impact on the treatment of cancer that we anticipated never materialized.  Not to say that we didn’t make progress, because we did.  Several treatments came out of that research, but none have been a smashing success.

Parallel to the research efforts in immunology, we made continued and substantial progress in understanding much more about cancer cells, their origin, and their internal processes. 

That research has led to a much better understanding of what makes cancer cells cancerous, and I have discussed the topic many times previously in this blog and elsewhere.  The targeted therapies resulting from that research have led to significant advances in cancer treatment, and the many targeted therapies in the research “pipeline” are testament to the effectiveness of those efforts.

Not to be forgotten in this discussion are the various efforts to produce an effective cancer vaccine—one that treats cancer, not one that prevents it—which have also been the topics of several blogs in the past.

Unfortunately, our vaccine efforts have not been particularly effective, although there are several promising developments that have been reported recently.

Cancer vaccines are also based on the same principle I mentioned above, namely trying to use the body’s own defense mechanisms to eradicate cancer cells by allowing our bodies to make antibodies or to “supercharge” our immune systems to recognize the cancer cells as foreign to our body, and in the process destroy the cancer.

The research reported today from the Surgery Branch at the National Cancer Institute is exciting for several reasons, which I will discuss a bit later in this blog.

The study was performed by Dr. Steven Rosenberg (who is probably the world’s expert on cancer immunology and related therapeutics and who has been working in this area for as long I can recall) and his colleagues, and is difficult to for most people to understand.

In fairly simple terms, the scientists knew that some patients with cancer had lymphocytes—which is a type of white blood cell that is the basis of our immune system—which recognized certain cancers as “foreign”, and were able to attack the cancer.

Unfortunately, for many patients with cancer, their lymphocytes do not have this capability.

What the researchers did in this study, essentially, was take some lymphocytes from patients with recurrent melanoma out of their bodies.  They then took those lymphocytes to the lab, and inserted genetic code into those white blood cells which gave the lymphocytes the capability to recognize certain tumor antigens (tumor antigens are unique markers on the surface of the cancer cell).  They then reinfused those genetically engineered lymphocytes back into the patients, after first treating the patients to significantly decrease the number of lymphocytes that had remained in the patients’ bodies after the first sample was drawn for the lab.  (This process of decreasing the remaining lymphocytes is called lymphodepletion, which in turn gives the transfused lymphocytes a better chance of survival.)

In order for this process to work, the researchers realized that they had to devise a technique where the infused lymphocytes would last long enough to do their job of recognizing and destroying cancer cells.  

Although their initial efforts were not successful at accomplishing this goal, they adjusted their approach and eventually did achieve success.

But success at having the lymphocytes survive and grow after they were given back to the patients was one thing.  To have an actual clinical benefit was quite another.

And that is one of the reasons this research is so exciting.

Melanoma is a skin cancer that in fact is very treatable if found early.  Unfortunately, that is not always the case.  And when melanoma recurs, it is very difficult to treat effectively with most patients succumbing to their disease.

Despite many years of trying different approaches, including a variety of immunotherapy techniques, we still have poor results with most patients with metastatic melanoma.

In this project, of 15 patients treated with the more effective approach outlined above, 2 of them had significant responses.  All of these patients had advanced melanoma, and all had failed prior treatments.

In the two patients who responded, one had disease in the skin and liver, and the other had disease in the lung.  Both patients responded to the gene/lymphocyte therapy, and both are now free of disease at 19 and 18 months respectively.

To be certain, 2 out of 15 patients having a response to a cancer treatment is OK, but it usually isn’t something very exciting when you consider the thousands of patients who need help in treating recurrent melanoma.

And, in the past, we have had similar reports of occasional responses to a new treatment which did not materialize into the hoped-for significant impact on particular cancers.

But let’s not lose sight of what has happened here.

First, this is the first genetic engineered treatment that I am aware of that has made it from the research bench (think mice and test tubes) to the clinic and demonstrated some degree of benefit for patients with a very serious cancer.

Second, this is what I call a “proof of concept”, meaning that the treatment has shown that it can work and hopefully, with further research and further refinement, more and more patients will be helped.  Not to mention that no significant side effects were noted.

Third, as the researchers note in the last sentence of their paper, “Engineering PBL (peripheral blood lymphocytes)…enables the in vitro (laboratory) recognition of tumor-associated antigens expressed on a variety of common cancers and the use of these genetically engineered cells for the treatment of patients with common epithelial cancers deserves evaluation.”

That complex sentence means that these researchers, based on their knowledge of cancer cells and the markers, or antigens, on the surface of cancer cells believe there is a real possibility that some of the common cancers we deal with--such as lung, breast, prostate and colon—may be amenable to treatment with this process as their research efforts move forward.

That is a bold statement, and I understand that these investigators are currently awaiting a green light from the FDA to move forward with their research on a broader scale.

For me, what is also exciting about this research is that it validates three decades of research effort. 

It melds several lines of investigation, including (among others) our improved understanding of the immune system, new understandings of how our bodies can genetically “code” to prevent cancer, and what we have learned about the targets in the cancer cell and on the surface of the cancer cell that offer us opportunities to develop new treatments.

Each of these areas on their own is exciting enough.  But to put all of them into one effort that produces results is outstanding.

We are encouraged by this report, and look forward to continued success.

Last night I found myself on the horns of a dilemma.

I am accompanying my wife on a trip to Kansas City as she gives a course for a medical professional organization.

Being the barbecue aficionados that we are, it isn’t particularly surprising that we would find our way to a local barbecue restaurant for our dinner last evening.

So there I sat, looking at the menu, and struggling with the question of what I should have for dinner.  After all, life is about choices: good vs. evil, pork, beef, chicken or—yes—fish (even barbecue restaurants these days make grilled fish available on their menus).

Maybe if I had read the articles and editorial that appeared in this week’s New England Journal of Medicine discussing the risks of premature death in relationship to body mass index, I would have made a better choice. 

But, I had not done my reading until this morning. 

The beef ribs won.

I have not made a secret of the fact that I have been working on overcoming some lifelong habits related to my health, my diet and exercise over the past 8 months.

In that regard, I am not unlike many of you who face the same issues every day.

I am fortunate that my wife and I have made a mutual commitment to eat better and exercise more, and we have made some definite (but slow) improvements over that time.  But, as we all recognize, it isn’t easy or simple to alter the habits and expectations of a lifetime.

Now we have some definitive information that is clearly going to be very sobering for many people: It is not just obesity that increases your chances of dying prematurely.  Being overweight increases your risk as well.  And the state of your weight at 50 may well strongly influence the state of your health—and your life—at 70.

For years we have known that being obese (defined as a body mass index, or BMI, of 30 or more) is associated with an increased risk of death.

What we haven’t been as certain about is whether being “just overweight” (defined as a BMI of over 25 and less than 30) is associated with similar increases in the risk of premature death.

As many of us age, and as our population becomes increasingly large, these questions are no small matter for our consideration.

I can still recall, when doing an interview on a radio show that I did back in Baltimore about 15 years ago, talking to a senior scientist from the National Institute on Aging who had just published a study suggesting that being a bit overweight was in fact not such a bad thing.

At that time, we used to have reference tables based on life insurance company data that told us what weights were associated with long life.

These tables were incredible, or so we thought at the time, with respect to what they described as a healthy body weight.

For many of us, including me, the tables implied that we had to look like stick people in order to be considered “healthy.”

Imagine how many of us felt when research suggested that these insurance tables were out of whack.  We were elated to hear that we could be a bit heavier and still be healthy.

In the meantime, we have developed more evidence about healthy body weights, and we have become much more comfortable using BMI as a tool to guide us.  (We need to remember that the BMI is not perfect, since people who are particularly muscular may score high on the BMI chart—think Sylvester Stallone and Arnold Schwarzenegger—yet still not have much body fat.  But I don’t think that most of us with a high BMI—even though we exercise regularly—need to worry about that as an excuse for our adiposity).

But we remain confused about the question of how much you can weigh and still not risk dying prematurely.

Even today, we can’t get the story straight, as reflected in two headlines discussing the new reports in the Journal:

“For men over 50, a few extra pounds not unhealthy”

Vs.

“Study: Even a few extra pounds is risky”

So which is it, my friends?

First, let’s acknowledge that even the best studies can sometimes be difficult to interpret in simple sound bites.  And, let’s acknowledge that each of us is unique, and sometimes it is hard to pigeon-hole ourselves into precise categories.

Each of us has our own history of weight ups and downs.  Some of us smoke, some of us don’t.  Some of us are former smokers and some of us never smoked.  Some of us drink alcohol, some of us don’t.  Some of us drink lots of it, some of us just once in a while.  Some of us exercise, some of us don’t.  Some of us think getting out of the chair and walking to the fridge counts as exercise, some of us think running a marathon is just a warm up.

You get the idea.  There are so many variables to consider that even the best study is only going to provide approximations.

We need to be aware that one study was based on a large number of folks from the United States, while the second study was based on people in Korea.  It may be difficult to extrapolate all of the implications of the Korean study to those of us in the United States.

Also, the studies are not necessarily reflective of the face of American in 2006.  Approximately 75% of the men and about 65% of the women in the United States study had more than a high school education.  The overwhelming majority of the participants were white.  The number of current smokers was less than is currently the case in the United States.

In the Korean study, only 14% of the women ever consumed alcohol, compared to 75% of the men.  Only 6.2% of the women ever smoked.

Putting those issues aside, the reality is that these studies represent the best compilation of data available to address the effects of overweight and obesity.

It simply isn’t possible for me to digest all of information in these studies.  I would hope that someday soon someone will develop a model similar to the risk scores we have for breast cancer in women that will allow us to “plug in” our information and come up with a mortality risk score.  Quite honestly, in my opinion, given the amount of information in these studies, it would appear that that shouldn’t be too difficult to do if someone has the interest and the financing to complete the task.

What the these reports say in brief is that what you have been predicts what will happen to you. Your weight at 50 is more important than any other factor, even taking into account the effective treatment of the various chronic diseases that eventually overtake most of us (think hypertension, elevated cholesterol, diabetes, heart disease and so on).

Here are the highlights:

• The risk of death is increased at both ends of the spectrum, for those who are significantly underweight—even if the low weight is not related to an underlying disease—and those who are overweight and obese. (Forget the old adage: you can never be too thin.  These data suggest that is definitely not true.)

• For men, being overweight in general was not associated with an increased risk of death, but being obese was.  Being overweight was associated with an increased risk of death in women.

• However—and this is the tricky part—if you are a man who has NEVER smoked, and you are overweight, your risk of death is in fact elevated if you are overweight, compared to smokers or former smokers were being overweight was not associated per se with an increased risk of premature death.  If you are a smoker or former smoker, being underweight was associated with an increased risk of death compared to non-smokers. 

• Smokers shouldn’t take any comfort in this information, since smokers in general do have lower weights.  But their smoking habit trumps the weight data, and they have a higher risk of death than other people at any level of weight.

• As we age, the effects of being overweight and obese on the increased risk of death diminish.  However, that is probably because there are premature deaths in people who are obese and overweight that occurred at earlier ages and leave the mistaken impression that those still alive are healthier.

• As we age, we become sicker.  The prevalence of chronic disease was 13.9% at age 50, 26.2% among folks who were 61-65 years old, and 33.1% among people who were 66-71 years old.

• For men and women 65 years of age and older, weight loss after the age of 50 was more strongly associated with the risk of dying than was weight gain

• Excess weight accounted for 7.7% of premature deaths among men, 11.7 percent of premature deaths in women, 18.1% of premature deaths among men who had never smoked and 18.7% of premature deaths among women who never smoked.

• And the final, bottom line: If you were overweight at age 50, as you age your risk of death is increased by 20% to 40% compared to folks who were at a healthy BMI between 23.5 and 24.9 (just below the category of “overweight,” which is a BMI between 25 and 30).

The Korean study echoes some of the findings from the United States study.  However, there are significant cultural and biological differences between the populations of the two countries.

In that study, they found that in the risk of death from respiratory diseases was higher among subjects with a lower BMI, even among non-smokers.  (It is important to note that the Koreans have a higher incidence of tuberculosis than found in the United States).

They also found that the risk of death from cardiovascular disease was higher among people with a higher BMI.

One interesting finding in the Korean study was that there was a higher white blood cell count among those with a higher weight, suggesting the possibility that underlying chronic inflammation in those who are overweight and obese may be another contributing factor to the increased risk of death in these circumstances.

So what do we do?  Does this mean that if we are overweight or obese and lose weight, we still have the associated increased risk of death?  If we are fat at 50, and have a normal BMI at 70 are these studies telling us that it doesn’t make any difference that we lost weight to improve our health?

The authors of the United States study are a bit pessimistic in this regard.  Their paper’s final sentence concludes on this somber note:

“Even against the background of advances in the management of obesity-related chronic diseases in the past few decades, our findings suggest that adiposity, including overweight, is associated with an increased risk of death.”

The editorial by Dr. Tim Byers that accompanies the two papers has a similar somber statement:

“The medical management of hypertension, hyperlipidemia, and insulin resistance certainly helps, but the treatment of these mediating factors does not completely eliminate the excess risk associated with adiposity…Our inability to negate these health risks may be due to the irreversibility of some of the biologic harm, our inability to achieve perfect control over the known mediating factors, or the effects of other as-yet-uncontrollable factors, such as the chronic inflammatory state of adiposity as is signaled by the association between white-cell counts and BMI in the Korean cohort study.”

But,  as Dr. Byers points out, “Fortunately, evidence points to a substantial health benefit from even small changes in weight trajectory, so the achievement of an ideal body weight need not be the primary goal.”

Dr. Byers goes on to recount his own experience trying to do a better job of getting his weight under control, and the fact that although he has made some personal progress, he still has a way to go.

Well, welcome to the club, Dr. Tim!!!!

By the way, the ribs were really good.  Although I had hesitated a moment before ordering them, my dinner guests didn’t help by reminding me that this trip to Kansas City was an important one for me, given my interest in barbecue and the fact that this is one of the world capitols of that particular genre of cooking. (The link to the Kansas City Barbecue Society wasn't working at the time of this writing.  Try www.kcbs.us)

They also reminded me that my wife and I had spent an hour on the treadmill (truly) just before we went to dinner.

So, I broke my rules and enjoyed the dinner.  We can’t expect ourselves to be absolutely perfect all of the time, which goes along with setting realistic expectations.

In that same spirit, we are now off to Arthur Bryant’s for lunch (for those of you not familiar with barbecue, this is one of the legendary ‘cue restaurants in the country).

Tonight we have an hour appointment with the treadmill, before going back to egg substitutes and salads tomorrow.

Oh, well…..

+++++++++

Postscript: 

My wife and I shared pulled pork, sliced turkey breast, and burnt ends at Bryant's.  All were excellent, and the pulled pork was the best we have had at a restaurant. The sauces were also very good. We didn't try their brisket, and we regretted that after we walked around to the back and talked with the cooks.  They told us they cook their brisket slowly at 150 degrees overnight to get it tender.  Guess we will just have to come back another time.

One of the most common questions I am asked is whether we are really making progress in our efforts to reduce the suffering and death from cancer.

There are many ways of saying “yes” in response to this question. 

Probably the simplest answer is to comment on the increase in the 5 year survival of people diagnosed with invasive cancers from 50% in 1974-76 to 65% for those folks diagnosed between 1995 and 2001.

However a better and more detailed examination of how effective our cancer control and treatment efforts have been over the past 15 years or so recently appeared in an article and accompanying editorial in the American Cancer Society’s journal Cancer.

The net result of the discussion was not a simple pat on the back.  The authors concluded that we have made progress; but we could do much better.

As noted in the article, in 1996 the board of directors of the American Cancer Society set a challenge goal for this country to reduce by half the number of deaths related to cancer between 1990 and 2015.

One important caveat that is often forgotten when our “2015 goals” are discussed is the fact that this goal was not a goal for the American Cancer Society alone.  It was a goal for this country.

By challenging the country to reduce the suffering and death from cancer, the Society was exhorting all of us to apply the information we already knew about the early detection and prevention of cancer, about the treatment of cancer, and about the causes of cancer to every aspect of our society and our health care system.  And, it presumed there would be continued research progress in each of these areas that, when applied, would contribute to achieving what was clearly an ambitious goal.

We are now at about the mid-point in the period of time allotted to make the goal.  So the natural question is, “How are we doing?”

The question was examined in detail by a committee of the Society, and that review formed the basis for the article.

Several themes emerged:

• Overall, there has been a sustained reduction in cancer deaths of about 1% each year

• Most of the progress has been made in the most common cancers that contribute to about half of all deaths from cancer (lung, prostate, breast, colon)

• Underlying health factors that affect the incidence of cancer have been addressed to some degree (for example, tobacco use), in other cases become more of a problem (obesity), and in other cases have had mixed effects (reduction in the use of hormone replacement therapy in post-menopausal women)

• We really could do a much better job of applying the knowledge we already know

The authors point out several interesting findings. 

In addition to the sustained, steady decrease in cancer deaths noted above, they also comment that the annual death rate from cancer has decreased by 23% from what would have been expected when comparing rates from 1990 to 2001.  That translates into more than 315,000 deaths that were either prevented or delayed as a result of everyone’s efforts.

To meet our 50% goal, however, at the present rate will take until 2040.  That is another 34 years instead of being achieved in 2015 as had been hoped for when the goals were set.

What do we need to do to improve this rate of decrease in deaths?

Tobacco is the single most important contributor to deaths from cancer.  Cancer of the lung and many other forms of cancer are caused by tobacco in both men and women. 

Even though we know this, we haven’t been as vigorous nationwide as we might have been with respect to tobacco control. 

Increased taxes, smoke-free environments, advertising and telephonic smoking cessation support services are but a few examples of what works in tobacco control.  Improve tobacco control, and deaths from lung cancer and other tobacco-related illnesses decline significantly, although perhaps over a longer time than we would like.

But budget cutbacks and other political considerations have prevented the progress we could achieve in these areas.

There is hope that some of the current prevention and early detection trials may provide some indications of benefit, and that could accelerate the decrease in lung cancer deaths.  But those trials remain “in progress,” and it will be several years before the results are known.

There are some interesting observations regarding colorectal cancer in the article.

For example, the authors note that deaths from colorectal cancer have been declining for some years, in part because of screening but also for reasons that suggest there may be factors other than screening that account for the decrease.

They provide the example of obesity, which has increased dramatically over the time period we are discussing. 

We know that obesity is an accepted risk factor for colorectal cancer.  Imagine that if we had not had the obesity epidemic, then perhaps the rate of colorectal cancer deaths would have declined even more than it has.

On the other hand, we also have known that hormone replacement therapy (HRT)  is associated with a decreased rate of colorectal cancer in women.  But in 2001, HRT was found to have several harmful side effects and the use of hormones dramatically decreased in post-menopausal women.

As the authors note, we are still waiting to see the expected increase in the rate of colorectal cancer in women as a result of large numbers of them no longer taking HRT.

But the major issue with colorectal cancer isn’t HRT or the fact that anti-inflammatory drug use has decreased since the Vioxx scare (these drugs are associated with a decreased rate of colon cancer). 

The major issue in this disease is that so many people don’t get properly and regularly screened.

If we did screen as recommended for colorectal cancer, there is one estimate I have seen that says we could save 35,000 lives a year.  That is more than half of the expected 55.000 deaths from this cancer in the United States this year.

In breast cancer, we need to dramatically increase our rates of screening if we are to improve our rate of death from this disease more than we have to date.  If anything, the data are suggesting that women are beginning to become somewhat more complacent about mammography as time goes on.  That is not a good thing.

The outlook for other cancers is not as good as it is for the four most common cancers (colon, lung, breast and prostate) according to the researchers.

For many of them, we don’t know their risk factors as well as we do for the more common cancers, we do not have particularly effective early detection methods, and our treatments are not as successful.

And we can’t forget that as our country gets ages, older people tend to put less emphasis on prevention and early detection, and that many cancer treatments are considered too toxic and unsafe for the elderly (although that opinion has been questioned by many, especially for those older folks who are still reasonably healthy and active).

One of the biggest challenges we face is how we make certain that everyone in this country has access to the information, the medical care and the support they require to either prevent cancer or find it at its earliest stage.

The authors note that we do not do a particularly good job of extending the benefits of our knowledge to all of our citizens, particularly those who live in poverty and have limited access to health care.

The report concludes:

“Just how much steeper the future downward slope in cancer death rates can be will depend on the extent to which policy makers and the American public can join together to create systems and incentives to reduce several behavioral risk factors for cancer (especially tobacco use and obesity), to facilitate early cancer detection (especially for colorectal cancer), and to assure that state-of-the-art treatment is available for all Americans who are affected by cancer.”

The editorial which accompanied the article applauded the progress described above, but notes that “we must accelerate greatly our current rate of progress.”

The editorialists go on to say that what we need to do now is not to so much worry what they describe as “headline-grabbing scientific and technologic breakthroughs,” but to figure out how to get what we already know into the places where that knowledge needs to be applied.

One of the questions they posed was, in my opinion, a key to understanding what is happening:

“If we cannot deliver what we discover and develop, then, as a nation, should we have spent the resources to discover and develop?”

We have spent immense amounts of public and private funds on research into cancer treatments and cancer prevention.  Yet, despite all we have learned, there remains a considerable chasm between what we know and what we do.

If you spent a substantial amount of your money to build a house, wouldn’t you want to live in it? 

That is basically what is happening in this country today when it comes to many aspects of the cancer prevention, cancer detection and cancer treatment.  We simply aren’t creating the networks and applying the knowledge in an effective manner that would provide many of our fellow citizens the benefits of what we already know.

If we could solve that puzzle through a better understanding of social, political and medical systems, we could do great things not only for cancer, but for many aspects of our health and economy as well.

We have the knowledge and have gone a long way to create the infrastructure to effectively reduce the burden of cancer in this country, as the editorial’s authors note.

In their words:

“The stage is set for significant reductions in cancer death rates, and the urgency has never been greater as we face the aging of the population and daunting increases in health care costs.  But realizing the promise depends enormously on how we apply the fruits of scientific inquiry to close the gaps between ‘what we know’ and ‘what we do’ to eliminate preventable cancer deaths; and ‘what we do’ depends fundamentally on effective, concerted will, advocacy, and leadership and on the power of broad societal alliances—among public health and health care leaders, policy advocates and policy makers, researchers, and the public.”

So we find ourselves at a crossroads. 

Are the ambitious goals the Society set for this country a decade ago just that—ambitious and unachievable—or are they goals that (with some concerted efforts) we can meet by the target date or close to it?

To me, the answer is obvious.  

2040 is simply too far away, especially when one considers that we already know much of what we need to know to make those goals close to a reality.

We spend a good deal of time discussing targeted therapies in cancer treatment, but don’t pay as much attention to what I am going to call “targeted diagnostics.” 

Yet, this is probably as important a part of the current revolution in cancer treatment since diagnostic and prognostic tests will play an increasing role in helping us improve our ability to decide which cancer patients will need treatment in which circumstances, as well as help us to more accurately provide prognostic information for patients and their physicians.

Two articles and an editorial in today’s New England Journal of Medicine point out how important these types of tests are becoming in cancer treatment.

Over the years we have developed a number of ways to help us identify which patients are going to do better or worse than others. 

For example, in most cancers, we are able to provide information regarding the stage of the disease.  In some cases the staging information is based on clinical data, such as physical examinations, x-rays, and so on.

In other situations, we have much more information available to stage a patient, such as surgical specimens of the cancer as well as the nearby lymph nodes.  When coupled with the clinical information, this can provide us with what we call the pathologic stage of the disease.

Some of the additional information that we can take into consideration in determining whether or not a person has a good or bad prognosis includes the information from the pathologist’s examination of the tissue under the microscope. 

The pathologist will comment in many cases whether a tumor is well or poorly differentiated, or perhaps whether or not the tumor invades blood and lymph vessels contained within the tumor.

There are some other laboratory tests that can be done which can help us determine the aggressiveness of the cancer, or whether it is likely to respond to certain therapies.

Still, these are imperfect ways to offer a patient a prognosis since there is no fundamental analysis of the cancer cells themselves. 

If we had this information, we might better predict who will do well, and who will not.  We may be able to understand why some patients who have tumors that we now predict will do well in fact have early recurrences, and why some patients whose cancers look aggressive in fact do very well.

For example, let’s examine what happens to a woman with breast cancer has no clinical evidence of spread of her disease.

The surgeon operates, and takes out the cancer and either one or many lymph nodes from under the axilla (depending on whether or not the sentinel node is positive or negative).

The pathologist then examines the cancer under the microscope, and tells the doctor the type of the cancer, whether or not it is well or poorly differentiated, and whether or not the lymph nodes contain cancer.

The pathologist also orders additional tests, such as hormone receptors, which provide both prognostic and treatment information (positive is better than negative; positive breast cancers have a higher likelihood of responding to hormone treatments).

The pathologist also does additional studies, such as HER2/neu markers, which help identify (again) good vs. poorer prognoses, and indicate whether a woman should be treated with Herceptin as part of her adjuvant therapy protocol.

But as good as these tests may be they really don’t examine the detailed genetic makeup of the cancer.  And, because of human and laboratory variability, not all pathologists and not all laboratories produce the same information from the examinations of the same material.

That’s where these new types of genetic tests come in.

By analyzing the genetic makeup of the cancer cells in a particular tumor, the hope is that we will have a better chance of determining how aggressive a particular cancer may be.

There are some very practical issues here that are worthy of consideration and discussion.

For example, we know that we treat many more women than we have to with adjuvant chemotherapy for breast cancer.  It’s not that we want to expose them to the toxicities, cost and inconvenience of chemotherapy.  The reality is that we do not have a foolproof way of sorting them into groups where we can say with reasonable certainty who will do well without chemotherapy, and who needs chemotherapy to improve their outlook.

The result is that we have to treat more women than who will benefit from the treatment, to be certain we don’t “miss” anyone who needs the treatment.

If we had a test that would help us identify which women had a better prognosis, and for whom adjuvant chemotherapy would add little or no benefit, then we would improve cancer care considerably.

In one of the articles in the Journal, the authors report on an evaluation of five different tests that are currently available either in the clinic or the lab which have been found to be useful in helping determine which breast cancer patients are at greatest risk of recurrence.

The simple explanation of this complex research study is that the authors found four of the five tests produced similar prognostic results.  This was interesting, since each of the tests looks at difference cancer cell genes and gene patterns.

The authors concluded that these tests, although looking at different genetic markers in the cancer cell, were in fact measuring the same “bottom line” cancer processes in the cells.

The editorial that accompanied the article made the point, as have others, that “at present, therefore, it is not clear that the quantification of the level of expression of dozens or hundreds of genes provides more information about the potential of a cancer for metastasis, virulence and response to therapy for an individual patient that does an optimal analysis of the standard and readily available histopathological prognostic factors.”

In plain English, although these tests are promising, they are not yet sufficiently accurate for patients and doctors to put their complete faith in the results for any individual patient.  They don’t significantly improve the information available to us in managing a breast cancer patient beyond what is offered by currently available technology.

As also pointed out by the editorialist, there are randomized clinical trials currently underway which are going to assess the practical impact of these tests

Until those trials are completed (and I suspect until more accurate tests are available), these genetic profiling tests for breast cancer remain an item of interest and may be informative for some patients. 

However, my oncologist colleagues tell me they are not yet sufficiently accurate for them to have complete comfort in recommending to their patient that they not take adjuvant chemotherapy for breast cancer based on a “good prognosis” result from one of these tests.

The article on the use of gene profiles in lung cancer was also interesting especially since, as the authors’ noted, previous reports of research in this area left uncertainty regarding the value of the use of these profiles in treating patients with lung cancer.  Consequently, in their opinion, theirs is the first study of its kind that has a practical application in helping doctors and patients make clinical treatment decisions.

In this paper, the authors did a very elegant analysis of multiple genetic profiles of lung cancer tissue from patients with two forms of non-small cell lung cancer (adenocarcinoma and squamous cell carcinoma).

Their test was reasonably accurate in predicting who would do well and who would not.  Again, however, it wasn’t perfect and there remains room for improvement.

One interesting finding was that in patients with stage IA lung cancer, which is a very early stage of the disease, the researchers were able to sort out who would do well and who would not.

In early stage lung cancer, most patients are advised to receive adjuvant chemotherapy based on clinical trials that show it has benefit.  But in stage IA patients, there is no proven benefit for adjuvant chemotherapy for the typical patient.

I suspect that we are going to be seeing more patients with Stage IA disease in the next several years, as more heavy current and former smokers decide to get screened for lung cancer with CT scans.

As a result, the issue of adjuvant chemotherapy may become more pressing, since 25% of these patients will relapse and die from their disease.

If that’s the case, then it would be valuable to know if we can predict which patients with stage IA disease are going to do well and who will not.  Then, we could consider what treatment options are available to help improve the survival for those patients who appear headed for a poor outcome.

What is exciting about this current gene-profiling research is that the authors were in fact able to sort the Stage IA patients into a group that did well, and a group that did not.

The implications of this finding were such that the authors suggested in the paper the design of a clinical trial to answer the question.  I certainly concur with their suggestion based on the results they obtained from their gene assay.

Where does all of this lead us?

First, I think it is important to understand that this type of research with its improved diagnostic and prognostic impact is part of a larger picture.

We are seeing incredible strides in the treatment of cancer.  This is in no small part the result of a huge investment in research that has helped us to understand the behavior of cancer cells.

The results, as recounted not infrequently in this blog, are showing up in many places, not the least of which is the development of the new targeted therapeutics.

But we are also developing targeted diagnostics, and targeted prognostic tools that will be able to tell us not only the details of the cancer’s behavior, but also which drugs to use to give the patient the best opportunity to survive their disease.

This brave new world was envisioned but not realized even a couple of years ago.

Now we are living in the midst of a revolution that will continue to develop and be refined at what I suspect will be a fairly quick pace.

Our doctors will be able to take cancers and perform analyses in the laboratory that will yield the secrets of these cells, and tell us who needs treatment and who does not, and then be able to monitor patients for relapse before the recurrent cancer becomes visible.

The studies reported in the Journal are but a very small sample of the type of research is currently underway in the area of genetic analysis of various cancers, and its applications to the care of cancer patients. 

It has taken us decades to get here, and I suspect the journey going forward will be considerably shorter.

I returned from vacation on Monday, and started the process of catching up on the emails and voice mails that had accumulated over the past 10 days.

One of the voice mails was from a lady I did not know.  I returned the call and spoke with the woman. 

I have been replaying the conversation in my mind ever since, because it reminded me of how difficult it can be for families and doctors alike when situations are not going well.  And it reminded me of how important it is for doctors and patients to communicate in times of crisis and in times of need.

She said in her message that she was aware I was on vacation, but could I please call her when I returned.  Her father was in the hospital with advanced prostate cancer and the doctors had told the family there was nothing more that could be done.  She wanted guidance and advice on what to do next.

When I called her (let’s call her Ms. M for the purposes of this discussion), she thanked me for returning her call.  But, she went on, it was too late. Her father had died the night before.

Mrs. M remained remarkably composed as she continued her story, and it was obvious that she was in need of sharing her experience with me.

Her father was in his 70’s and was a man of faith and principle, she said, who imparted wisdom and compassion to his many children, all of whom revered him, loved him, and learned from his counsel over the years.

He had been diagnosed with prostate cancer, which apparently had spread.  He started a course of chemotherapy but had not fared well.  He was being treated at a major cancer center (one I personally hold in high regard).  He had side effects from the chemotherapy, and then developed pneumonia.

So far, this is not an unusual story.  An unfortunate and sad story, but not unusual.

Then came the comments that were unsettling to me, describing her father’s last days.

The family could see that he was not doing well.  They tried to get information but couldn’t find anyone to spend time with them to discuss the situation in understandable terms.  The doctors told the family there was nothing more they could do for their father, and that they needed to get him out of the hospital.

“But surely, Dr. Lichtenfeld, there must have been something they could have done! Instead they just sent him out of the hospital to die,” she said.  (Mrs. M. told me that her father was transferred to another hospital, and was there for a couple of days before he died.)

But here was the part that was especially difficult for her:

She told me about the doctors making daily rounds.  She said they looked like they were in their late 20’s or early 30’s.

“And every day they would come into the room and say to my father that he was dying, that he didn’t understand that he was dying, and that his family didn’t understand he was dying.  Dr. Lichtenfeld, they could have said it once.  We could see he was dying.  Why did they have to say it again and again, day after day?”

I imagine the reason this discussion made such an impact on me is that I had spent some time on vacation reading Tim Russert’s new book entitled “Wisdom of Our Fathers: Lessons and Letters from Daughters and Sons.”

It is a wonderful and poignant book, consisting of brief vignettes from people around the country talking about what made their fathers special to them.  Ordinary men doing simple, extraordinary things that provided their children with memories for a lifetime.

I was deeply touched by many of the stories in Mr. Russert’s book, and Mrs. M’s comments fit perfectly into the picture that so many of us have of our fathers (and our mothers).  To Mrs. M, her father was a very, very special person.  In her eyes, the doctors didn’t care about that at all.

I will be the first to admit that I have only heard one side of this story.  I suspect the doctors would have a different version.

Perhaps the family, being so large and so devoted, pressed the doctors hard for information they didn’t have, or perhaps they had unrealistic expectations for the treatment, or perhaps they didn’t appreciate what time the doctors did spend with the family. 

Then there is the sad reality that metastatic prostate cancer, when it no longer responds to hormone therapy is in fact difficult to treat under the best of circumstances.

All of that is possible. 

However, what this daughter is left with is an impression of doctors that didn’t care, a staff that couldn’t respond, and the loss of a father who meant so much to so many.

It is not easy being an oncologist. 

When I started my practice, a large proportion of the patients were hospitalized for treatment and the side effects of the treatments.  Their physical and emotional needs were substantial. 

Sometimes I could meet those needs; sometimes I couldn’t.  I suspect that there were many occasions where people said the same things about me that Mrs. M is saying about her father’s doctors.

That didn’t mean I didn’t care, because I did.  Sometimes there were so many family members calling my office that I had to ask that someone be designated to be the “lead” contact for the family.  Otherwise, the time spent talking to one family could overtake the need to talk with other families.

Every death was a loss that was difficult to accept.  As a doctor, you don’t get used to that finality (or, at least, you shouldn’t).

But I can’t recall many situations where the family wasn’t prepared for the inevitable, or felt that we hadn’t done what we could with the limited resources we had available at that time. 

For many, although their loss was painful, death was not unexpected and it occurred with dignity (thanks in no small part to a very dedicated staff of professionals of all types who cared for my patients, and who were at the vanguard of community cancer care).

I can’t tell you how much it meant to all of us when families, in their moments of greatest sadness, turned to us and comforted us with words of thanks and kindness.  For them, the battle had ended; for us, we had to immediately turn to the next patient and the next crisis.  There was so little time to grieve.

I was saddened by Mrs. M’s call, and what she experienced.  We talked about her dad, and we talked about what fathers mean to families, and what they mean to children.  We talked about finding strength in the many wonderful memories her father left her and her family, and how—with time—she will be able to reflect on the positives of his life as opposed to the negatives of his death.

We talked about how one day those younger doctors will be older doctors, and how perhaps they too will begin to understand that beyond the person in the bed is a life filled with history, a family that cares, and memories that are special. 

And that even in the most dire of circumstances, a doctor must give hope and comfort even when they know they can’t give life.