A Possible Breakthrough: Personalized Treatment for Hodgkin's Disease

My friend and colleague, Jose Costa, and I recently had an opportunity to write an editorial about  an exciting paper by Steidl et al.  published in The New England Journal of Medicine on March 11, 2010. I thought it would be worthwhile reprinting some of our commentary here because I think the data may be what we've been looking for when it comes to changing the direction of the treatment of Hodgkin's disease. 

The data provided by Steidl and his colleagues, in fact, offer the breakthrough we have been looking for to select patients with a particularly poor prognosis, regardless of stage, for more-aggressive treatment and bring more logic to the treatment of this very curable malignancy.

Steidl and his co-authors discovered a gene signature of tumor associated macrophages and monocytes in patients with Hodgkin’s disease that correlated with outcome. Remarkably, they were able to validate the correlation in an independent cohort of patients using CD 68—an immunohistochemical marker of normal macrophages. 

  
The correlation of CD 68 positive macrophages with outcome was striking. All patients with limited disease, minimally positive for CD 68, were alive and free of disease at the time of the report. The association of CD 68 positivity and disease specific mortality rates was strong in all subsets analyzed. In advanced disease the correlation between macrophage number and progression-free survival is significant.

This study provides a rationale for the use of molecular tools when effective treatments are available but we cannot prospectively separate those who will be cured from current treatment from those who will not respond. 

Hodgkin’s disease is a good example of this type of situation. For almost 40 years now, early stage disease has been curable by radiotherapy, and combination chemotherapy can cure both early and advanced-stage disease. Despite an overall cure rate of around 80%, treatment has stagnated in the past two decades because of the absence of precise markers that can predict response to therapy. As a result of this situation most patients, especially those in early stages of disease, are over treated— they receive radiotherapy and combination chemotherapy. As a consequence, long term toxicity from treatment is significant. 

In some studies where young women have received both chemotherapy and radiotherapy, the incidence of beast cancer reaches almost 30% at 15 years after treatment. Almost all patients with classic Hodgkin disease will go into remission with initial treatment but about 30% of patients with advanced disease and almost 15% of those with early stages of disease will also relapse. Early relapses in patients with both advanced and localized disease treated with chemotherapy defines a drug resistance subset of Hodgkin’s lymphoma. This group carries a very poor prognosis through all subsequent treatment approaches including high-dose treatment with stem cell support.

It is of considerable interest that early relapse from complete remission carries the same poor prognosis in all tumor types where remission is possible, suggesting a common mechanism of resistance across tumor types. If at the time of diagnosis we could identify the small subset of Hodgkin patients who are destined to fail to respond to chemotherapy, most patients could be spared the use of a combination of modalities as initial treatment, especially radiotherapy, that is associated with long-term toxicity.    

The Reed–Sternberg (R-S) cell is unique amongst lymphoma cells in that a number of important signaling pathways have been shown to be constitutively activated, including the JAK-STAT, receptor tyrosine kinases, NF-kappa B and other pathways^. The R-S cell also secretes numerous cytokines, including granulocyte-macrophage colony-stimulating factor, which may be responsible for the assembly of inflammatory cells in involved lymph nodes. It has been termed the master regulator of the surrounding inflammatory response.

Almost all tumors types are invaded by macrophages and it was once thought that this invasion represented a host immunological response to the tumor. However, most evidence now links tumor-associated macrophages (TAM) with a poor prognosis, as demonstrated in the study by Steidl and his colleagues. Termed ‘tropic macrophages,’ TAMs bear a close resemblance in function to embryonic macrophages associated with cell migration during development.These macrophages have been shown to mediate blood vessel formation by regulating the angiogenic switch through secretion of VEGF and hypoxia inducing factor.

Migration of macrophages to areas of the tumor seems to be a late event in Hodgkin disease. It is difficult to explain the impact of trophic macrophages on response to treatment unless at some point in the evolution of the disease, a critical pathway to apoptosis is crippled in the R-S cell and this is associated with the secretion of a cytokine that leads to macrophage infiltration of the tumor. Such an event could inhibit cell death in response to cytotoxic treatments. 

Rationing Health Care is Bad for Cancer Patients

       The current bill before  the house and Senate does a disservice  for cancer patients. It is not correct to say,  " it's true that some people are covered well, but many are not" as I have heard said by people who should know better. It's more correct to say that ,"most Americans  are covered well in the current system." This is especially true of cancer patients. So be careful what you do to change it.
      Cancer patients suffer most when they try to change jobs and are denied health care in a new job because of a preexisting  condition or when the amount they can spend on health care is capped. Like most Americans, they are also concerned about cost of insurance as well.

      In prior postings I exposed the numbers game used by those who support this bill for what it was, a bogus use of numbers to scare the American people into reform they don't need and don't want. There are not 47 million Americans uninsured. Even President Obama has begun to use a lower figure, 30 million,  a little embarrassed , I think , to be caught  using a number no one bothered to check ( this is still an overestimate). The American Cancer Society should feel some embarrassment for doing the same thing.

     But what is as clear as can be is that there is no way the current House and Senate proposal can stay within budget without rationing care. And people I know close to the administration say to me " get real, Vince, rationing is coming". They barely hide this although they don't trumpet it for fear of scaring more people away. They do admit to the need to cut billions from Medicare though.
     The preferred method to decide what to ration is to use "Comparative Effectiveness Research"(CER) to decide what should be approved. A billion dollars has been allocated in the bill for this. The best way to characterize CER is to say that it compares yesterday's therapy with that of the  day before yesterday. It is always behind the curve. The newest approaches need not apply. Cancer patients always get the short end of the stick when care is rationed.
      Look at the UK's National Institute of Clinical Excellence ,(acronym ,NICE -British doctors refer to it as "not so nice"). Their decision to deny coverage for the use of the drug Erbitux in patients with head and neck cancer was one example of  a feckless disregard for cancer patients. There are more. Studies have shown an enormous, statistically significant, difference in survival for those who are irradiated with Erbitux compared with those who don't receive it. Yet they denied coverage.  They actually don't even question the data, they just say it is not cost effective to use it. In other words if you have the misfortune of having head and neck cancer in the UK, you are not worth saving.
      This is the system the bill tries to emulate. It includes commissions to determine standard of care ( in the cancer field, " standard of care" is a moving target ) and authorities to the secretary of HHS that would allow her to limit the use of new technology even without  CER, as NICE did in the UK with Erbitux. The new drug from Plexicon, to which every patient with metastatic melanoma should have access, wouldn't even be considered for CER.
      They know they will need to ration care to pay for this version of health care reform. At the most exciting time in the history of cancer research, when new clinical advances are being made every day in the cancer field these provisions would  stop clinical innovation in its tracks.

      What is needed for the cancer patient is a stepwise approach that preserves the best of the current system and provides more security . Like most people I could write a bill in  ten pages to do this, not the  2,700 pages in the current bill.
      Prevent denial of coverage for a preexisting conditions, remove caps on the amount of coverage and allow insurance to be purchased across state lines. This would do it for cancer patients and save hundreds of millions of dollars as well.
       It's the many mandates included in some state's policies that drive up cost. Purchasing across state lines would allow more people to buy less expensive policies that suit their purposes. This might mean giving up some of our precious  mandates but  isn't it is better to cover more cancer patients well, than force policies on them with too many mandates that are too expensive to buy? 

      Frankly I don't see any organizations purported to be speaking for the interests of cancer patients telling the congress the specifics of what they need and, most especially ,what they don't want. We need the three things mentioned above and we do not want  a system that will require rationing of care .

     Oh , and by the way, the Congressional Budget Office estimates the new bill would still leave 10 to 19 million people uninsured , which is more than are truly uninsured now.

What happened to the merit sytem in NIH peer review?

There was an article in the New York Times on 22 September by Gardner Harris entitled “Debate flaring over Grants research”.It was based on a recently released report by the GAO on how NIH manages its grant program.

The essence of the NYTs articcle was whether or not NIH grants administrators are right to reach down to “make exceptions “to fund grants with worse scores, to support new young investigators. They say the average age of investigators has risen from 35 in 1980 to 41today, so such steps are necessary. The American Cancer Society goes even further. Anyone over the age of 45 need not apply.

 What happened to the merit system? If your goal is to find new knowledge that leads to the eradication of disease shouldn’t we be funding the best and the brightest whatever their age?

Harris says “ There has been a growing chorus of complaints over the years that the agency's scientific review process is deficient-that is fails to finance high risk research; that projects must effectively be half done before financing is approved; that cliques control the process; and that reviewers are rarely the field’s leading lights”.

Anyone involved in the NIH grant system knows all these complaints are true. I speak from experience; I ran the largest chunk of that grant program at the NCI for 15 years.

The essence of the problem is that universities are addicted to Ro-1 grants. The grant system has become an entitlement program. Without a Ro-1 grant it is difficult for an investigator to attain tenure. What has surprised me, even shocked me, and is that what an investigator does with those grants is often secondary to the fact that they got them. Supporting high-risk research is not the major goal.
The grant peer review process has become the major arbiter of tenure. And incumbents do have an unfair advantage. Peer review committees, each made up of grantees, give the edge to established investigators like themselves. And, scientists will always admit to other scientists, (but not in public) that they don’t submit their best and newest ideas in a grant but ideas that have some data to support them- . It’s a bit of grantsmanship.

Left to their own devices, young investigators do well on their own. Their ideas are often fresh and, in a purely merit system, they can out compete an incumbent. But the way the system is now constructed they are at a disadvantage but it is a disadvantage of NIH’s own making.

The NIH distorts the system even further. It decries “targeted research” but it regularly influences the research process by issuing Request for Applications in specific (targeted) areas with set aside funds. The areas selected are what the Congress or some NIH staffer, or a board of advisors, thinks is the best way to spend grants monies. I have watched young investigators change their research interest not because they thought an RFA identified an interesting area but because they needed to follow pools of money to get a grant. So much for NIH's storied primacy of “investigator initiated research”.

And more gamesmanship. To keep Congress anxious about how many grants are funded each year NIH artificially keeps the percentage of approved grants funded very low. NIH scores grants on a system of 1 to 5 with one being the best and 5 the worst score. A grant can also be disapproved. Few ever are. Many are , however, given scores of 3, 4 or 5 that indicate they shouldn’t be funded even if the investigator is young and money is available. Or expressed another way, no matter how much money we had, we could find better ways of spending it than funding grants with bad scores. Instead of funding only 21 % of all approved applications, many of which shouldn't be funded,  we are more often funding 40 to 50 % of the good applications. Not too bad really. Reaching down could get you into bad territory.
It would be interesting if data were available on the age distribution of the PI's of grants that score better than 2 compared to those that score worse than 2.

It is in the best interests of both universities and the NIH to leave the system as is. But, NIH has so distorted the peer review process that it is faced with dilemmas like funding young investigators just because they are young not because of the merit of their ideas. The grant system has become an end in itself instead of a means to an end.

A Churchill quote about Democracy is often paraphrased to defend the current system as “the worst system ever invented except for every other system”. This may be true for democracy but not the NIH peer review system.

MORE ON THE NUMBER UNINSURED IN THE US

There was an exchange on the floor  of the house chamber between the President and Congressman Joe Wilson last night that bears on the figure of the number of people who are uninsured in this country.
The data used comes from the US census bureau and is 47 million.  I used the 47 million  figure to point out the various groups that make up this number using the same census bureau data. The 47 million figure includes 10 million people who , according to the Bureau , are " not American citizens".
Last night the  President vehemently said that his plan would not include the funding of health insurance for illegal alliens.
The President's speech should now automatically  lead everyone to reduce the figure of those without insurance  to 37 million..  Will it? I doubt it since it would tend to  reduce the urgency  to take down our entire health system for a mere 37 million uninsured, made up of four additional groups whose probelms can be solved by simple legislation. Actually , this morning he actually increased it!
As I said in my recent footnote to that blog, when it was reposted, I use these figures as a way to  judge whether any speaker actually knows what he or she is talking about vis a vis the health care issue..
So far it is slim pickings and it doesn't include the President or his advisors..

Note: I worte the following post in 2007 using US census figures for that year but it is relavent today. I have found that anyone who uses the "47 million are uninsured "argument  is usually as wrong about everything else the say about the health care system so I have decided to re  post this.
VTD


 I am concerned about the direction of the current debate on the reform of our health care system. Most proposals for reform are based on two premises.

The first, is that our health care system is overrated and not equal to some that use a different model for health care , like the single payer systems of the United Kingdom and other European countries.
The second is that 47 million Americans are "uninsured".
Neither , in my view, is correct. Both come from the unfortunate tendency to tear something down when proposing something new. Afterall ,who will take a proposal to fix something seriously unless the something is totally broken.
It is the second premise I want to address here because the phrases "47 million Americans are uninsured", or " without insurance whatsoever" are used as if this was one homogeneous group to show that the american health care system is broken.
So , let's look at the makeup of the 47 million figure dervied from the US Census Bureau figures.
1. 27 % , or roughly 12.7 million people, are uninsured for only a part of the year in which they are counted but are ultimately insured. This is an issue or portability of health insurance. This group will need plan A to reduce their risk of becoming ill while not covered by insurance . But are they really " uninsured" in the way the term is usually used?
2. Roughly 10.3 million of the 47 million are listed as " not American citizens". They require Plan B which surely has more to do with immigration reform than reform of the health care system. Most proposals use the 47 million uninsujred total but ignore the fact that a substantial part of this group are illegal aliens.
3. The third group is made up of roughly 9 million people, half of which make between 50 and 75 thousand dollars a year and the other half more than 75 thousand dollars a year. Many of them are healthy young people who can afford insurance but do not wish, for various reasons, to buy it. This group, if they must be covered, would require a plan that required everyone to buy health insurance, say, Plan C.
4. In the 4th group, there are roughly 8 milion people of all ages, adults and children alike, who are actually eligible for health insurance under a variety of existing plans but don't take advantage of them , again, for a variety of reasons, sometimes out of ignorance. Surely we can solve the problems of educating people about the existence of these plans using Plan D.
That leaves the 5th group, roughly about 7 million people, who might be called the " hard core uninsured" or "without insurance whatsoever", certainly a tragedy for a country as rich as ours . This group will require Plan E.
But the 47 million uninsured figure is quoted as if all of them are hard core uninsured which is factually incorrect .
It is important , it seems to me, to examine the issues related to these groups separately, and to hear specifics about plans A through E so we do not apply " the general solution for the specific problem" and do more harm than good to the finest health care system in the world..

Speaking of New Orleans

There was a story today in the New York Times about how this magnificent city is clawing its way back trying  make itself better than it was before hurricane  Katrina and  with some success.
It reminded me of  a bad decision the leadership of the American Society of Clinical Oncology ( ASCO) made to  drop New Orleans from it's list of meeting sites.
When someone commented that New Orleans would no longer accommodate a meeting the size of ASCO, I checked with a colleague of mine in New Orleans and was assured it wasn't true. The convention center , hotels and New Orleans outstanding  eateries are well able to handle the meeting.


I was told by ASCO's  EVP Alan Lister, that it was primarily a financial decision . ASCO can make more money from the exhibits at the Chicago convention center than at New Orleans because of the way it's configured. But it turns out New Orleans is not suffering from discrimination .  ASCO is gong to be in  Chicago in perpetuity despite  good facilities at other cities as well.

Now don't get me wrong, I like Chicago-just not every year. Not to mention that ASCO could do it's part  by helping the economy of New Orleans.

I told the ASCO leaders that I thought if the ASCO members were polled  they would probably  have voted for  variety over Chicago in perpetuity.

Annoyance was obvious. I was told it was a board decision to make. As a member I disagree.
I was at the founding meeting of ASCO. The society was founded for the benefit of its members, and had as it's primary role  the dissemination of information, not to become a bank.
I don't suppose the annual budget to run  the society of 90 million dollars had anything to do with  this?

The Slippery slope

I read with great interest the story in the 30 August Sunday Magazine section of the New York Times  on the  tragedy at Memorial Hospital in New Orleans in the days following hurricane Katrina.
If the story is accurate , patients who would have been difficult to move or who had signed a " Do not Resuscitate Order" ( DNR) were euthanized by lethal injections on a grand scale.
The doctors involved justified it by saying the police told them if they were not out by 5 PM on that last day they would be left behind . And they wouldn't have survived anyhow.
There were clearly patients who were conscious and not ready to die  and those who had signed DNR orders as a statement, not because they were terminal.
Now the surgeon who administered the lethal doses of drugs is campaigning for laws that would exempt doctors from liability if they did these things under emergency conditions.
And, of course, the doctors were not indicted  even though euthanasia is illegal.  New Orleans politicians, it appears , had decided they had had enough bad  exposure.
I mention  this because it is an example of what can go wrong if you give doctors the right to judge who should live and who should die. I am a cancer doctor and know physicians who believe that patients who have metastatic cancer should be left to die anyhow, with dignity of course, but early. My worst nightmare has always been to wake up from a cancer operation and find one of these guys looking down on me. I would not have wanted to be a cancer patient at that  hospital after Katrina.
Giving doctors that power is a first step down a slippery slope, especially if we end up with a government run health care system and rationing.