Thursday, November 8, 2012
WVCI ASH 2012 Abstracts
ASH abstracts are out. I recently posted on how to carefully evaluate the news. Over next several weeks I want to draw attention to those abstracts that I think are most noteworthy. In the meantime, I thought I would put the links to the studies our center has participated in. Most of these represent collaborations with leaders in CLL and NHL. It has been a good year in CLL/NHL and I think we are really on the verge of substantial change in the field.
Monday, November 5, 2012
How I treat Diffuse Large B Cell Lymphoma (DLBCL)
In contrast to the debate about how to select initial
treatment for patients with follicular lymphoma, treatment in DLBCL is
considerably more straight forward.
These two lymphomas represent the most commonly diagnosed subtypes of
NHL. For further questions about thedifferent types of NHL link here.
Most patients with DLBCL are going to be treated with
R-CHOP. I have a lengthy post about this regimen that describes the regimen in detail for the interested reader. There are a number of considerations that may
individualize therapy for some patients so it is not just a blanket – one size
fits all.
When R-CHOP is the selected regimen, several important
questions need to be asked. The first
question is “how many cycles.” In most
patients the answer will be six. I
normally repeat CT scans after cycles two, four, and six. If the patient still has measurable disease
and it continues to shrink between cycles four and six – I will occasionally go
to eight cycles – but that is definitely the minority of patients. You cannot continue R-CHOP indefinitely
because the “H” which stands for “hydroxydoxorubicin” aka “Adriamycin” can be
hard on the heart and you can only give so many doses before running into long
term cardiac issues.
For the less common patient who shows up with “limited
stage” (ie. Stage I or stage II disease mostly in one spot), you can consider a
shorter duration of R-CHOP when combined with radiation. Usually 3 cycles followed by radiation is
enough. Sometimes that is more difficult
when the site of disease is less agreeable to radiation such as in the colon.
I will also use radiation in patients who present with stage
III, or IV disease provided there was one spot that was particularly bulky at
the start (>10cm) but this is a little more controversial. This tends to reduce the likelihood that
disease will relapse at the same site of disease, but does not necessarily
prevent distant spread of the lymphoma.
The next question is whether a patient is at risk for their
lymphoma coming back in their brain.
Since chemotherapy does not get into the brain very well, it is a site
of relapse in a minority of high risk patients.
This includes patients whose initial disease started in the testicle,
the nasal sinuses, or someone who has a lot of disease outside of their lymph
nodes (what we call extra-nodal disease).
For those patients with high risk of CNS relapse, we have the option of
administering a shot of a drug called methotrexate by way of a lumbar
puncture. When done by our radiology
colleagues using fluoroscopy, this doesn’t typically bother a patient too
much.
The problem with methotrexate is that we really don’t have a
lot of confidence that it works particularly well. It is one of those things we do by convention
when what is really needed is a change of convention. Some docs will actually give a much higher
dose of methotrexate into a vein. The
dose in this situation typically requires the patient be admitted to the
hospital for a few days. This may be a
more effective strategy, but obviously a lot more difficult to perform.
There are circumstances where R-CHOP may not be a good idea
for a patient. In patients with prior
exposure to Adriamycin (perhaps for a breast cancer many years ago), or who are
starting with a bad heart to begin with, you may need to substitute the
Adriamycin for something more “heart friendly.”
Sometimes these substitutions are done for patients that you think might
be a little too old or fragile to handle R-CHOP. I did recently treat a 92 year old with
DLBCL giving him six cycles of R-CHOP.
Granted, he was still out there chopping wood – but another example of
where age does not equal limitation. He
is two years out from therapy now and just celebrated his 70th
anniversary – way cool!
There are a number of ways to do swap things around. I know some docs who use a different
formulation of Adriamycin known as “Doxil” which is more heart friendly. Others have used a drug with a lot of
similarities to Adriamycin known as mitoxantrone. Unfortunately, this substitution reduces
efficacy and it isn’t totally clear that it protects the heart all that
much. I have periodically used a
substitute for Adriamycin known as etoposide.
The published study for this is pretty old and I cannot be certain it is
a great substitute. I try to use R-CHOP
as much as I can, but sometimes you just have to avoid the Adriamycin.
Another key group of patients for whom I choose a different
path are the patients with “double hit” lymphoma. I need to explain some biology here. There are common DNA abnormalities in
DLBCL. The most common is where a gene
known as BCL-6 gets abnormally activated by getting the chromosomes rearranged,
resulting in excessive protein. This can
happen with other genes including BCL-2 or Myc.
When a lymphoma has two of these (most commonly Myc and one of the
others), we think these patients do not do as well as our more common “single
hit” DLBCL. Most scientists agree this
group is considered “higher risk” but what to do about it is less agreed upon
and subject of practice patterns not necessarily scientifically proven to be
any better.
When Myc in locked on, the cells cannot stop dividing. We see exceptionally highly proliferative
tumors in this setting. We can measure a
“Ki67” which is just a marker for dividing cells. While normal DLBCL might be anywhere from
40-80% of cells staining positive, Myc affected cells are almost always >
90%. Myc is also a hallmark of a
particularly aggressive version of lymphoma known as Burkitt’s lymphoma. Unfortunately, if you show microscopic slides
of very aggressive lymphomas to a bunch of pathologists, you will find a
surprising degree of disagreement as to whether a lymphoma is Burkitt’s or
DLBCL. In fact there is even a new
category known as “Aggressive B Cell lymphoma with features indeterminant
between Burkitt’s and DLBCL.” The main
point for me, is that we sometimes under-diagnose either double hit lymphoma or
it’s close cousin Burkitt’s and instead call it DLBCL.
Clinical science gets a little thin here so please do not
take the following as the only acceptable strategy. For those patients with highly proliferative
tumors, I will use a regimen that has been studied in both DLBCL as well as
Burkitt’s. The regimen is known as
“R-EPOCH” A lot of the letters (as well
as the drugs) are actually the same. In
fact, there is only one new drug – etoposide.
The main difference is that all the drugs are infused over four days
through a pump followed by some injections on day five. This is different than R-CHOP which is
commonly given over just one day.
Since the regimen is good in Burkitt’s as well as DLBCL, I
use it when there is gray area with the diagnosis. I cannot say that this is definitively the
right thing to do but I know a number of academic physicians who do the same. There is a large research study currently
comparing R-EPOCH to R-CHOP but it is accruing slowly and I don’t know if it
will ever give us the answer as to which regimen is the best.
R-EPOCH is also my preferred regimen for those patients with
HIV who have been diagnosed with DLBCL.
This is a unique subpopulation that used to be a lot more common than it
is today. There have been a number of
studies using this regimen in this setting.
Hopefully that should cover a number of questions about how
to select a front line regimen in DLBCL.
It is not meant to be a replacement for your own doctors advice but
hopefully give you confidence that your doc is on the right track. I hope I’ve highlighted where things are
pretty clear and where they are controversial so that any differences in
strategy might be explainable.
Thanks for reading!
Jeff
Tuesday, October 30, 2012
ASH abstracts are coming... beware of the headlines
It seems like we hear a lot about clinical trial results that are “significant.” Yet, in many cases it feels like the outcomes of certain diseases really are not changing all that much. ASH abstracts will be out in the next few weeks and it is always a time for news. Unfortunately, much of the news is poorly reported because the language of science is not always the same as the language of the rest of the world. Nowhere is that more important as the word "significant." When the headlines scream "significant" it really helps to understand what is actually being communicated.
We often trumpet a study that has achieved a level of improvement to be
considered “statistically significant” yet what that really means is that when
two or more interventions were compared, the difference in outcome between the
interventions is unlikely to have occurred by chance (or more accurately
stated, likely to have occurred by random chance <5% of time should the
study be repeated multiple times under similar circumstances).
The problem with this definition is that a small difference
between interventions (say an improvement in response rate from 33% to 38% or
improvement in survival from 11 months to 12 months) can be “statistically
significant” if it is observed in a large enough population whereas most
patients might say – “who cares if it is such a small difference.” This is a key point, so I want to make sure
it is clear. If you see a 5% difference
in a study population of 70 patients, you might agree that there is a good
chance the difference is purely random.
On the other hand, if you see a 5% difference in a study population of
10,000 patients – chances are that is a real / reproducible difference. In the latter case, we would call that “statistically
significant” even if the patient says, “so what.” Take a 50% difference in outcome however, and
even if it is observed in a small population, it is a big enough difference to
make you think it isn’t a random chance observation.
When we design studies we go through an exercise known as
“powering the study” which enables us to project a difference between two interventions
and then calculate how many patients we will need to study to enrolled to
conclude that our difference is “statistically significant.” If we project that a new treatment improves
response rate from 20% to 80% that is a huge number and we need few patients to
prove our point. Similarly if we double
the duration of response with a new treatment – that doesn’t take many patients
either.
When the difference is small though, the studies have to get
very large. That is true when we already
have very effective treatments (hodgkin’s disease) and you don’t have a ton of
room for improvement (ie, can’t cure 130% of patients) or the incremental
benefit is small (different hormone manipulations in breast cancer improving
outcome by 1-2%). One good clue to how
meaningful a result is is simply to look at how many patients were
enrolled. If you have > 500 patients
per arm, chances are the improvement is fairly modest.
Patients want “clinically meaningful” results such as “Dad
survived 6 years instead of 6 months with his pancreatic cancer” or “everyone
who takes the new drug feels better and responses are dramatically
improved.” Who could blame patients for
wanting this.
Over the past 50 years most of our advances have fallen into
the “incremental gain” category. This is
where we had huge studies to show that we could prolong pancreatic cancer
survival by two weeks on average and this was trumpeted as “statistically
significant” – yuck! We’ve had a bunch
of these recently in colon cancer. Seethis link for a very good article about this.
Sadly, the route to approval of drugs requires
“statistically significant” even if it is not “clinically significant.” Of course, a new drug is going to be very
expensive and if you have to take $90,000 of treatment to prolong life by
several months, you might think twice if you were paying for it (provenge in
prostate cancer). The British have a
system that measures “clinical significance” as part of their approval
process. I have to say that I can see
some logic there – please look at this link for more.
I am pleased that many of the experimental treatments in CLL
fit the category of “clinically meaningful.”
It is important to note that randomized studies to measure the magnitude
of difference have not been completed with ibrutinib, CAL-101/GS-1101, ABT-199,
GA-101 and so forth – but they are underway.
Many thought leaders feel these agents will be both “clinically
significant” and “statistically significant” to boot. Hopefully we will gain broader access to
these soon and patients will live longer, happier lives.
ASH abstracts are just around the corner. You will probably hear a lot about “significant”
results. Pay close attention to the use
of the terms “statistically significant” and “clinically significant” – they are
different. Look for how large the sample
size is in the study. Lymphoid studies
tend to be smaller than breast / lung studies.
A big lymphoma study or CLL study might be >500 patients. Keep in mind that you cannot define “statistically
significant” unless you are comparing at least two groups – so they are either
randomized studies or looking at subgroups within a larger study.
Hopefully we will have a lot of studies to discuss that
really improve the quality of lives for patients with these disease.
Statistic vs real significance
drug cost vs efficacy
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