Dr. Francine Foss, Living with Lymphoma
August 2, 2009
Welcome to Yale Cancer Center Answers with Drs. Ed Chu and Francine Foss, I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center and he is an internationally recognized expert on colorectal cancer. Dr. Foss is a Professor of Medical Oncology and Dermatology and she is an expert in the treatment of lymphomas. If you would like to join the discussion, you can contact the doctors directly. The address is canceranswers@yale.edu and the phone number is 1888-234-4YCC. This evening Dr. Chu welcomes his co-host Dr. Francine Foss for a conversation about lymphoma.
Chu
Francine, before we discuss the main topic of lymphomas, can you
tell our audience a little bit about what made you decide to focus
on lymphomas as your treatment specialty?
Foss
I have been interested in lymphoma pretty much from the time I
started my medical training. I think it relates to the fact that I
have always been interested in the blood and white blood cells for
some crazy, crazy reason. When I was at the NIH I got very
involved in the lymphoma program and in fact I took over the T-cell
lymphoma program there, both the clinical as well as the research
component.
Chu
As we have said before on the show, you and I trained together at
the NCI a number of years ago and what was really special back
then, and maybe a part of why you decided to focus on lymphoma, is
that at the time we were there the National Cancer Institute was
the leading place, the Mecca, for developing new treatments for
Hodgkin's and non-Hodgkin's lymphomas.
Foss
That's right Ed, and in fact, Vincent DeVita who was our leader at
the NCI at that time and has subsequently come to Yale Cancer
Center, was one of the major leaders in developing the treatments
that we use today for lymphoma. In addition to that, at the
time that I was there the NCI did a very important pivotal study
exploring whether or not chemotherapy and radiation therapy was
beneficial for patients with low-grade lymphoma. This has been a
landmark study to help us to know how to treat those patients even
today, 20 to 25 years later.
Chu
Maybe you can tell us what lymphoma is and what the different types
of lymphomas are that people should be aware of?
Foss
Lymphoma is really a generic term and it incorporates a number of
different diseases. A lymphoma is a disease of white blood
cells; however, unlike leukemia, which is also a disease of white
blood cells, lymphoma predominantly occurs in lymph nodes or in
organs like the liver or the spleen, whereas leukemia primarily
occurs in the bone marrow and in the blood. Lymphoma comes in
a number of different varieties. There is B-cell
lymphoma,
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which is the more common type and is about 85% of the non-Hodgkin
lymphomas. Then there is the T-cell type, which is 15%, and
then there is another whole category called Hodgkin disease, which
comprises about 25% of lymphomas. All of these lymphomas have
different subtypes under those general categories as well.
Chu
It has gotten a lot more complicated since you and I were fellows
back at the National Cancer Institute.
Foss
That's right, and it's becoming even more complicated now that we
understand the genetics of some of these types of lymphomas,
because what we are now doing is dissecting them even further and
identifying subgroups based on different kinds of genes that are
expressed, or different patterns that the cells express. We are now
taking categories and making more categories and more categories,
and the real value of that, particularly from the point of view of
a patient, is that we are learning that the treatment for some of
these categories is different.
Chu
Obviously we have been aided a great deal by our understanding of
the basic biology and the molecular genetics of these different
lymphomas.
Foss
That's right, and in fact, lymphoma is one area in cancer where we
have developed a lot of novel approaches and where we were first
able to understand the genetics and subgroup two different types of
lymphomas in the diffuse large B-cell category that have completely
different prognoses. Also lymphoma is the disease where we first
learned how to use monoclonal antibodies, and in fact rituximab,
which is for B-cell lymphoma, was one of the first antibodies that
came into the clinic.
Chu
About how many people each year are diagnosed with Hodgkin's and
non-Hodgkin's lymphomas?
Foss
The American Cancer Society estimates that there are about 53,000
cases of non-Hodgkin's lymphoma in the United States. That
basically translates into over your lifetime, you have about a 1 in
50 chance of developing these lymphomas.
Chu
Wow.
Foss
95% of those are in adults by the way, and 5% are in children.
Chu
What do we know about the causes for the lymphomas?
Foss
We know a little bit more about the causes of lymphoma now then we
used to. One of the
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things that we have learned is that there are certain viruses that
can predispose patients to lymphoma, and those include viruses
called EBV virus and also the hepatitis viruses in some cases can
be causative. We also know that other environmental
conditions can predispose people to lymphoma. For instance,
we know that if you have an infection in your stomach called H.
pylori, that can predispose you to a lymphoma of the stomach, and
we also know that there are certain environmental exposures that
can lead to lymphomas or other diseases, particularly chemical and
pesticide exposures.
Chu
It is interesting that farmers who are exposed to pesticides and
herbicides, especially in the Midwest, seem to have an increased
risk for developing non-Hodgkin lymphomas.
Foss
That's right, and one of the interesting things that we have
learned, and in fact this was discovered at the National Cancer
Institute while we were there, is that if you look at those farmers
in the Midwest that are exposed to a lot of herbicides and
pesticides, we can actually detect abnormalities in their
chromosomes before they develop lymphoma. Not all of those
patients will develop a lymphoma, but clearly we can link a
chemical exposure with a chromosomal abnormality in the genes and
then later development of lymphoma. This is also pertinent, by the
way, for Vietnamese veterans who were exposed to Agent Orange,
because we know that Agent Orange exposure can lead to the
development of both Hodgkin's disease as well as non-Hodgkin's
lymphomas.
Chu
Over the past few years there seems to have been an increasing
incidence of non-Hodgkin's lymphomas. Do we know why that may be
happening?
Foss
There are a number of reasons for that. One of which is that
the incidence of developing a lymphoma increases as you get older,
and with the baby boomer generation aging and we are all living
longer, there's a greater chance to develop lymphoma; that's number
one. Number two is that as we all know, there are many more
toxins in our environment in terms of exposures in the air, in the
water, everywhere, even in the food that we eat, and one cannot
help but think that that's contributing to the increased incidence
of lymphoma. Also, one could think about the increased frequency of
some of these viruses in the population that might also be leading
to the development of the lymphoma.
Chu
Is there any genetic component to the development of lymphomas?
Foss
There isn't as clear-cut a genetic component to lymphoma as there
is with other cancers, say like colon cancer for instance, but we
do know that there are familial clusters of lymphoma and we also
can see lymphomas in these family cancer syndromes where other
members of the family could have ovarian cancer, colon cancer, or
lung cancer. Certainly there is some
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genetic component to the disease, and with respect to the
genetics, I would like to just mention one other thing that's
really interesting. That is that the group at the National Cancer
Institute and at Yale have been working together for years to look
at the genetic predisposition to cancer, and particularly to
lymphoma, and what we found is that there are certain types of
genes or patterns of gene expression, what we call snips, that
actually predict who is going to develop a non-Hodgkin's lymphoma.
A lot of these genes are related to the immune system and how our
body responds to various toxins.
Chu
That's interesting. Are these tests easy for an individual to be
tested for, these snips, as you call them?
Foss
Yes, in fact this only involves saliva or a blood test. A
major study was done in the State of Connecticut where they
collected samples from over 2000 patients and normal controls, and
that's the so-called "hair dye study" that you may remember from a
number of years ago where they thought there might be an
association between the use of hair dyes and non-Hodgkin's
lymphoma. Subsequent to that study, hair dye preparations
have been changed, so everybody can relax about that, but in the
course of collecting that data, we learned a lot about the genetics
of lymphoma in this population.
Chu
Let's switch gears a little bit and talk about the common symptoms
that an individual who is diagnosed with lymphoma may present
with.
Foss
Lymphoma is an interesting disease because it can present with very
significant symptoms, or no symptoms at all. In fact, many of
the patients that we see come into our office because they noticed
a lump, or their primary care doctor, in the course of a normal
exam, noticed a swollen lymph node. Some of those patients
also come to us because there was an abnormality in their blood
test. For instance, they may have had an elevated white blood
count or they may be anemic. On the other side of the coin
are the patient's who come in with aggressive lymphoma or
symptomatic lymphoma, and generally speaking, those patients can
have weight loss, fevers, night sweats, or they can have other
symptoms that are related primarily to the growth of lymph nodes
that might be putting pressure on other organs and causing those
symptoms.
Chu
A common complaint would be swollen, tender lymph nodes in ones
neck for example. What would you tell someone who may be listening
right now who has fever, sweats, and has a very tender lymph
node?
Foss
Well, we all have to remember that the most common cause for a
swollen lymph node, a sore throat, fevers and chills, is an
infection, and in fact, what most primary care doctors do is
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observe those patients and maybe treat for an infection.
Then, if those symptoms don't resolve themselves over the course of
a couple of weeks or a month or so, and the lymph node is still
swollen, in that case you might want to seek medical attention and
be a little bit more aggressive. But there are certain
conditions like mono, which we are all familiar with, where you can
have swollen lymph nodes for weeks or months, and that doesn't
necessarily mean that you are going to develop a lymphoma.
Chu
So the good news for our listeners out there is that in the vast
majority of cases where you have got swollen lymph nodes, it is
really probably nothing to worry about.
Foss
Exactly.
Chu
What would be the different types of diagnostic methods that you
would use, or consider, in trying to make a diagnosis of
lymphoma?
Foss
The primary diagnosis of lymphoma is made based on examining a
piece of tissue under the microscope, and that usually involves
getting a lymph node biopsy. However, if the lymph nodes are
all internal, what we can do is what we call a needle biopsy where
we just pass a small needle in and we obtain a piece of tissue.
Chu
Now, who would usually do that diagnostic procedure, that
biopsy?
Foss
The biopsy is either done by a surgeon or by interventional
radiology. It is important to note that when you do get a biopsy,
that biopsy needs to undergo a number of different steps with
respect to looking at the pathology because it can be tricky
sometimes to distinguish lymphoma for what we call a benign
lymphoid proliferation.
Chu
And I imagine that as we have a bit more understanding of the
molecular genetics and there is a much deeper understanding of the
molecular classification of lymphomas, clearly it is going to be
important to have a pathology group that is very sophisticated in
the types of diagnostic techniques that they have at hand.
Foss
Exactly, and as I mentioned at the beginning of the show, we are
now dissecting these lymphomas into categories based on different
genes that they express. We can look at a number of these different
parameters just by looking at the tissue under the microscope
because we have special stains. We also can do molecular studies on
this tissue to look for the expression of certain genes that will
help us to categorize those lymphomas, and that directs our
treatment.
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Chu
You are listening to Yale Cancer Center Answers. I am here
in the studio with Dr. Francine Foss, my co-host, and one of the
nations leading experts in the treatment of lymphomas. At this
point we are going to take a break, and at the outside of the break
we are going to then focus our discussion on new treatment
strategies for lymphomas.
Chu
Welcome back to Yale Cancer Center Answers. This is Dr. Ed
Chu and I am joined by my co-host Dr. Francine Foss discussing the
approach and treatment strategies for lymphomas. Before the break
we were talking about how to make a diagnosis of lymphoma, Francine
can you talk a little bit about the different types of x-rays and
imaging studies that go into helping us evaluate a patient with
lymphoma?
Foss
Sure, and that's a very-very important point with lymphoma because
the way we treat it really depends on the stage; stage meaning how
far it has spread. We look at patients from the point of view
of stages I through IV. We determine the stage based on
x-rays of the lymph node groups at the liver and the spleen. We
used to use CAT scans for that and now we have a new and more
sophisticated test called the PET scan, which is actually much more
sensitive at detecting very small amounts of lymphoma in lymph
nodes. So we do a PET scan along with a CAT scan and we are able to
look at nodes that light up using the PET tracer
and we also look at the CAT scan to see if those lymph nodes are
enlarged. We are also able to see the other organs with PET
scan and we can see whether there is involvement of the bone or
soft tissue such as the skin. All of that information goes
together to come up with a clinical stage.
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Chu
What is the overall prognosis for patients with lymphoma? I
imagine it must be in some way correlated with the stage of the
disease.
Foss
The prognosis for lymphoma is highly variable and it depends on the
type of lymphoma that you have as well as the stage. For
instance, patients with a low-grade B-cell lymphoma have a survival
that's really the same as a normal population, so they could have
this disease for 25 to 30 years, and in some cases, not even
require treatment. On the other side, there are the very
aggressive lymphomas which require immediate treatment and in some
cases with some of the aggressive T-cell lymphomas, the survival is
not good even after conventional chemotherapy type approaches.
Chu
Maybe break down what the general treatments strategies for an
individual who presents with lymphoma are?
Foss
The treatment for lymphoma can involve anything from watching and
waiting, in the case of low-grade lymphomas, to potentially using
radiation therapy for patients that have localized lymphomas, to
the use of chemotherapies, conventional chemotherapies, such as a
single-agent drug like fludarabine or a combination such as
CHOP. In some cases, we use more aggressive combinations such
as EPOCH which require hospitalization, and in
some cases we even go to a more aggressive approach which is to
follow the chemotherapy with a stem-cell transplant. There are many
patients with lymphoma who will receive both radiation and
chemotherapy, and then after that the treatment is not over for a
lot of patients because we do maintenance therapy, particularly for
patients with low-grade lymphoma where we know that the use of the
monoclonal antibody rituximab can prevent those patients from
recurring.
Chu
It sounds like in your description that there is no role for
surgery at all in the treatment of lymphomas?
Foss
That's a very good point, and it's something that a lot of patients
ask about. They say, "I have this lump, why don't we just take it
out?" Well, we know that lymphoma is a systemic
disease. Even if we only find it in one place, we know those
cells can travel around in the blood, so taking one lymph node out
isn't necessarily going to solve the problem. In fact, in patients
with localized lymphoma, where we take out one node because we make
a diagnosis and we find nothing else, often times we will
follow that up with either involved radiation to that area of the
body, or may be even something like rituximab or some
chemotherapy.
Chu
Over the last few years we have talked a great deal about the
development of target therapies, in particular for breast cancer,
lung cancer, and colorectal cancer, my own area of expertise,
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but without question targeted therapy really has a very
important role in the treatment of the lymphomas.
Foss
That's right, and as I mentioned, the CD20 antibody rituximab was
really the first targeted therapy to be used in this county, and
that is for patients with B-cell lymphomas. One of the things
about lymphomas is that they are basically white blood cells and
they do express a lot of proteins that we can generate antibodies
against, but the problem is that the normal cells may also have the
same antigens. So the trick is to administer a targeted therapy
that's going to kill the tumor cells without killing too many of
the normal cells. Now, we are lucky with rituximab, because
that seems to work, but there are other antibodies that we have
developed for lymphoma, such as antibodies against the CD4 protein,
that eliminate not only the tumor cells, but also lots of the
normal cells as well. I would like to put in a plug for
T-cell lymphomas here because it really is the most
underrepresented lymphoma in terms of research in the United
States. If you look at the number of cases of T-cell lymphoma
it is 9500, and the number of cases of Hodgkin's disease is
actually 8500. There are more cases of T-cell lymphoma than
Hodgkin's disease, but if you ask the average person on the street,
they have heard of Hodgkin's disease, but many people do not hear
very much about T-cell lymphomas. Unfortunately, T-cell lymphomas
can be among the most deadly lymphomas.
Chu
You also have been very actively involved in, as I said, developing
new treatments, and in fact you played a leading role in the
approval of a number of new agents that are approved for these
T-cells lymphomas.
Foss
That's right, we developed the first fusion toxin which
specifically targets a lymphocyte, and that's the ONTAK molecule
that targets the CD25 receptor on T-cells. This has proven to be a
very important molecule in the treatment of patients with both
cutaneous T-cell lymphoma and now aggressive T-cell lymphoma.
We have taken this molecule and combined it with chemotherapy for
patients with aggressive PTCL and we have shown that their response
rate is very high, much higher than with chemotherapy alone, and
now we are trying to exploit this strategy to combine that targeted
molecule with others so that we can specifically target pathways in
the lymphoma cell that will lead to cell death.
Chu
Do we know, Francine, why the lymphoma develops, or focuses on the
T-cell as opposed to the B-cell?
Foss
The interesting thing about T cells is that our body uses T cells
for what we call immune surveillance. In other words, there
are T cells living in all of our tissues and those T cells
recognize foreign antigens or proteins and generate an immune
response. For instance, in the mucosa, in your mouth and in
your stomach, in you intestines and in your skin, there are
lots
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of normal T cells and so you could think about that in terms of
the chance of a cell becoming mutated. If there are lots of T
cells that are always looking for foreign proteins, they are
dividing quickly and if they are turned on then there is a greater
chance that you are going to develop a problem or a mutation and
then develop a lymphoma, and in fact, we do see T-cell lymphomas in
a lot of these extra-nodal sites such as the skin, the GI tract,
the liver, the mouth for instance, and so they tend to be atypical
in terms of their presentation.
Chu
Interesting, tell us a little bit about the role of radioactively
labeled antibodies because that's becoming a very hot area.
Foss
So to speak.
Chu
Right.
Foss
Radioactive antibodies have been used in the treatment of B-cell
lymphoma, and again, we've used the CD20, which is the antigen that
the rituximab molecule targets. We have basically taken that
rituximab antibody and hooked it up to radioactivity in the form or
either an yttrium or an iodine isotope, and the reason we have done
that is that the antibody can act as a carrier to deliver the
radioactivity specifically to the sites of tumor, and then that
radioactivity can be very powerful in terms of killing those cells
say in lymph nodes and in other sites of lymphoma.
Chu
Does that radioactive label ever get clipped off and cause problems
with normal tissues?
Foss
It's interesting because you and I were both at the National Cancer
Institute when we first started to develop these radioactive
antibodies, and in fact, one of the problems we had in the first
clinical trials is that there was a dissociation between the
radioactivity and the antibody, but the technology has improved
significantly since that time such that now that does not appear to
be a problem at all. We do not detect any free isotope that's
not hooked up to the antibody.
Chu
Is there ever any concern that if a patient is treated with
radioactive antibody, that their family members or their friends,
or relatives may be exposed?
Foss
This is obviously a big concern and the Nuclear Regulatory
Commission is involved in our use of these antibodies in the
clinic, and what we know is that the exposure to radioactivity to
other people is very minimal. The major risk that we run is really
in the first 24 to 48 hours and we generally tell patients not to
go home on a bus and don't have a child sit on your lap, maybe you
want to stay in your room for 24 hours, but pretty much after that
you are safe to
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be exposed to people.
Chu
Francine, tell us a little bit, as we are kind of a heading towards
the end of this interview, about the clinical research that you are
focused on at Yale Cancer Center.
Foss
We have a significant number of trials now available for patients
with both B-cell and T-cell lymphomas, and we are focusing on
developing novel therapies for patients. For instance, we
have a trial looking at the use of histone deacetylase inhibitors,
which is a novel molecule in patients with both B and T-cell
lymphoma. We are also developing a strategy to use small molecule
inhibitors of tyrosine kinase in lymphoma. We are now opening a
study using a molecule called sorafenib. In addition to that,
we are looking at the use of transplantation and we are developing
novel strategies to do transplant in patients with both B and
T-cell lymphoma. Our major focus is really on trying to
develop novel therapies, but also learning how to use some of the
drugs that are currently available in different ways.
Chu
Maybe a quick word about the transplant work that you were doing
when you originally were at Tufts-New England Medical Center, and
then coming here to Yale you helped to develop a very novel
approach to try to prevent graft-versus-host disease, which is
still a very significant problem in stem cell transplantation.
Foss
That's right, and in fact, if you look at the overall outcome after
transplantation, particularly for lymphoma patients, the major
cause of death is really the complications of transplant. So we are
looking at using a treatment called photophoresis with the
conventional transplant regimen and our outcomes using that
approach have been excellent.
Chu
Francine, the time has gone pretty quickly and we are at the end of
the show. Obviously we look forward to having you come back and
talk more about new treatments for lymphoma.
Foss
Thank you Ed, it's been a pleasure to talk with you tonight.
Chu
You have been listening to Yale Cancer Center Answers and I would
like to thank my co-host and tonight's guest expert Dr. Francine
Foss for sharing her expertise on the treatment of lymphomas.
Until next week, I am Ed Chu from Yale Cancer Center wishing you a
safe and healthy week.
If you have questions or would like to share your comments, go to yalecancercenter.org where you can also subscribe to our podcast and find written transcripts of past programs. I am Bruce Barber and you are listening to the WNPR Health Forum from Connecticut Public Radio.