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