Treatment Innovations for Esophageal Cancer

Drs. Daniel Boffa and Jill Lacy, Treatment
Innovations for Esophageal Cancer July 5, 2009Welcome 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 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 1-888-234-4YCC.  This evening Ed and
Francine are joined by Dr. Daniel Boffa, Assistant Professor of
Thoracic Surgery, and Dr. Jill Lacy, Associate Professor of Medical
Oncology.  Both Dr. Boffa and Dr. Lacy are experts in the
treatment of esophageal cancer.Chu
Let's start off by defining for our listeners what is esophageal
cancer?Boffa
 Esophageal cancer is an abnormal growth of the cells that line the
esophagus. The esophagus is the swallowing tube that starts at the
back of your mouth and goes through your chest and into your
abdomen where it connects your intestine with your stomach. The
cancer is a loss of the ability of a cell to control its own
growth, so not only does that cell grow out of control, it loses
its borders within the neighboring cells and not only grows through
the tissues of the esophagus, but can enter the blood stream and
spread throughout the body.Foss
Jill, esophageal cancer is one of the fastest rising cancers in the
United States.  Can you talk a little bit about what causes it
and what the incidence is in the United States?Lacy
This dramatic increase in the incidence of esophagus cancer is due
to an increase in one type of esophagus cancer called
adenocarcinoma. Since 1975, the annual incidence of adenocarcinoma
in the United States has increased by a dramatic 400% and this was
at a time when the incidence of the second major type of esophagus
cancer, called squamous cell carcinoma, had been decreasing. 
What's behind this has been referred to as an epidemic of
adenocarcinoma of the esophagus, but the reality is that we really
don't know for sure.  We think it may be related in part to a
rising prevalence of acid reflux disease.  We do know that
long-standing chronic reflux of stomach acid up into the esophagus
can cause precancerous changes in the lining of the esophagus,
something called Barrett's esophagus.  And Barrett's, we do
know, is a very significant risk factor for ultimately developing
adenocarcinoma of the esophagus.  We also think that obesity
may be at play here as well.  There is very strong
epidemiologic data that links obesity and an increased body mass
index to an increased incidence of esophagus cancer, as well as a
number of other cancers. There are still many unanswered questions
about why we have had this dramatic increase in incidence of
adenocarcinoma of the esophagus.3:15 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3Foss
Dan, can you tell us how many cases there are of this in the United
States and what age groups are primarily affected?Boffa
 There were about 16,000 new cases last year in the United
States.  The majority of patients are in their seventh or
eighth decades, so in their seventies, late sixties, through their
late seventies, but that being said, all ages, all adult ages, can
be affected by this. We see this in patients in their thirties as
well as patients in their eighties.Chu
Jill, can you go through some of the main risk factors for
developing esophageal cancer?Lacy
There are a number of factors that have been clearly identified
that increase the risk of developing esophagus cancer, and these
risk factors actually differ significantly between the two major
types that I have referred to; adenocarcinoma and squamous cell
carcinoma.  For squamous cell carcinomas of the esophagus
there are two major risk factors, tobacco use and alcohol
consumption, and each of these independently increases the risk of
squamous cell carcinoma, and when used together, the risk is
actually significantly amplified.  The patients or individuals
who are at highest risk of developing squamous cell carcinoma are
individuals that are cigarette smokers and smoke heavily, and also
heavy drinkers of hard liquor. Their risk is about 100 fold over
the general population.  Some of the other risk factors
associated with squamous cell carcinoma include poverty,
malnutrition, diets low in fresh fruits and vegetables, or certain
vitamins and minerals.  Now, the story is different for
adenocarcinoma.  There, the major risk factors are
long-standing acid reflux disease, or GERD, and it is linked to
Barrett's esophagus and Barrett's is really the major risk factor
for adenocarcinoma.  Obesity also is a risk factor as I had
mentioned.  Tobacco is only a moderate risk factor for
adenocarcinoma and it increases risk by about two to three fold.
Alcohol does not appear to be a risk factor at all for
adenocarcinoma in contrast to squamous cell carcinoma. In fact,
there is recent data that suggests that drinking wine may actually
have a protective effect on the development of adenocarcinoma,
although certainly that needs to be validated and would not be
considered a reason to go out and start consuming wine.Foss
Barrett's esophagus is a term that we have heard is a risk factor,
and I believe that's primarily a surgical issue, so something that
you would address, can you talk about it and what to do about it if
you have it?Boffa
 Barrett's esophagus is the body's response to seeing conditions
that it wasn't designed for.  The body was meant to propel
food in a one-way direction, and that's forward.  When
patient's get reflux disease, the esophagus is exposed to things
from the stomach that it wasn't designed to see, specifically acid
as well as some bile acids, and in response to this, the esophagus
is injured and tries to protect itself by reverting to a type of
lining that looks6:43 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3
 like the intestine downstream of the stomach that normally sees
the gastric acid all the time, and that sounds like a good
idea.  Unfortunately, once it converts into this
intestinal-type lining, it loses control over its ability to
regulate its growth and overtime that Barrett's can actually be
transformed into something called dysplasia, where Barrett's is a
metaplasia, which is a stage change to a different kind of
lining.  Dysplasia is a change to a more irregular, less
controlled lining, and that's what's really at risk of converting
into a cancer.  If you have Barrett's esophagus, we really
don't know exactly the best way to treat you for Barrett's. 
It is more of a marker of a potential to form a cancer.  If
you took everybody that has Barrett's esophagus, that group is more
likely to have cancer, but it's on the order of about half a
percent per year.  You don't need to rush off and have your
esophagus removed just because you have Barrett's.Chu
Dan, what would the symptoms be that would typically be associated
with say someone who has developed, or is beginning to develop
Barrett's esophagus?Boffa
 Patients who have frequent heartburn who are on acid suppressive
medicines like Zantac and Pepcid are at risk to develop this
Barrett's because they are having things reflux into their
esophagus and are at risk to develop this metaplasia.  About
14% of all patients who have significant reflux that are taking
daily acid suppressive medicines will develop Barrett's.  On
the other hand, 20% of patients with Barrett's have no symptoms at
all.  If you do have symptoms of gastroesophageal reflux
disease and you are taking acid suppressive therapy, it is
reasonable to have an upper endoscopy at some point to assess
whether or not you have this change.  It's something that you
can actually see when you do an upper endoscopy, it's a microscopic
change that leads to a different appearance of the lining, so just
by looking at it you can tell if somebody has Barrett's.  If
you do have it, then you need to be followed more closely because
you are at an increased risk for esophageal cancer.Foss
If you get scoped and you don't have Barrett's, and you continue on
those acid suppressing medications, can you be reassured that you
won't develop Barrett's, or do you need to be scoped on a frequent
basis to prevent that?Boffa
 That we don't know.  We have ways of sort of categorizing
risk, and unfortunately, nobody's risk of esophageal cancer is
zero.  Having a long-standing reflux disease, we don't know
exactly how much reflux you need to have before you develop
Barrett's.  I would say that if you have a negative upper
endoscopy, that is reassuring, but if you continue to have
long-standing reflux disease getting a follow-up upper endoscopy
five to ten years later is probably a reasonable thing to do. 
Unfortunately, we don't have enough information to give hard and
fast guidelines, but you should definitely be in contact with the
gastroenterologist if10:20 into mp3 file 
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 you do have gastroesophageal reflux type symptoms, even if you
have had one negative upper endoscopy.Chu
Jill, once esophageal cancer develops, what are the typical
symptoms associated with that, is it similar to say the symptoms
associated with Barrett's esophagus?Lacy
Well there is some overlap.  The overwhelming majority of
patient's, about 75% with esophagus cancer will present to their
physician with the complaint of food getting stuck and difficulty
swallowing, what we call dysphagia, and that is usually progressive
over a few weeks to in some cases months.  It can be
associated with weight loss due to decreased intake of food in
about 50% to 60% of patient's, and significant or dramatic weight
loss is an adverse prognostic factor in terms of outcome. 
Only about 20% of patient's actually complain of pain when they
swallow, what we call odynophagia, and we have been talking about
acid reflux.  About 20% to 30% of patient's will give a
history of long-standing, and in many cases severe, acid
reflux.  Rarely, patients will present with more advanced
disease with a cough, difficulty breathing, hoarseness, and
recurrent pneumonias, but that's much less common.  I would
emphasize that, and this has already been emphasized by Dan, that
acid reflux is extremely common in our population and so, just by
virtue of having acid reflux it doesn't mean that you are going to,
or ever will get esophageal cancer, and similarly dysphagia,
although it certainly needs to be evaluated, it can be caused by a
number of benign conditions as well.Foss
Jill, as you were talking, it occurred to me that a lot of these
symptoms are things that many people have. How often do you see
somebody coming in very late, who has had these symptoms and kind
of chalked them up to something else?Lacy
It certainly happens, I think most patients when they are having
difficulty swallowing, and food is hanging up, will consult with
their physician within a reasonable period of time.Chu
And if any of these symptoms should pop up, who should the
individual seek attention from first, should it be their primary
care physician, should it be you or Dan, the surgeon, a medical
oncologist? Can you take us through the process of who these
individuals should see?Lacy
If someone is noticing for the first time difficulty swallowing or
severe acid reflux symptoms, they probably should start with their
primary care physician and undergo an evaluation there, and then he
or she can make appropriate referrals to a gastroenterologist and
go from there.13:18 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3Boffa      
      
 If you are having difficulty swallowing, I think that you really
need to have an upper endoscopy or barium swallow, and in general
most general practitioners are very aggressive at pursuing the
diagnosis of esophageal cancer.  However, if somebody is with
their primary care physician and doesn't feel that it is
progressing, then they should feel free to contact a
gastroenterologist themselves or a surgeon themselves.Foss
Thank you for that Dan.  We are going to take a break
now.  You are listening to Yale Cancer Center Answers and we
have Dr. Dan Boffa and Dr. Jill Lacy discussing the treatment of
esophageal cancer.Foss
Welcome back to Yale Cancer Center Answers.  This is Dr.
Francine Foss and I am joined by my co-host Dr. Ed Chu, and Dr. Dan
Boffa and Dr. Jill Lacy, experts in esophageal cancer from Yale
Cancer Center.  Dan, we talked a little bit about the risk
factors for esophageal cancer and Barrett's esophagus.  Can
you tell us how esophageal cancer is diagnosed?Boffa
 Esophageal cancer is diagnosed by a biopsy and it's performed
during an upper endoscopy. One of the themes that we will try to
convey to you is the importance of being cared for by a center that
has experience with esophageal cancer.  The condition we have
mentioned before of Barrett's esophagus has a tendency to convert
to something called dysplasia, which can either be low or high
grade dysplasia, and that just reflects the degree to which the
cells have become abnormal, it can look very much like a cancer and
the diagnosis can be difficult to establish.  At Yale we have
pathologists who are specialized in reviewing esophageal cancer
cases and its important that more than one pathologist examines a
biopsy to establish the diagnosis of cancer.16:22 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3Chu
Jill, once the diagnosis of esophageal cancer is made, what goes
into the evaluation process to determine whether or not the cancer
is localized or perhaps more advanced?Lacy
Once we have a diagnosis, its important to stage the patient and
that means determining how big the tumor is and whether it's spread
to any other sites in the body.  Staging is very important as
it determines our treatment and it also determines prognosis. 
Staging for esophageal cancer is based on three aspects of the
disease, one is how deeply the tumor in the esophagus actually
penetrates into the wall of the esophagus, the second component is
whether the tumor has spread to the surrounding lymph glands or
lymph nodes in the region of the esophagus, and then the third
component is whether the tumor has spread to distant sites in the
body such as the liver, lungs, or bones, and from those three
components we use a 4-tiered staging system, as we do in many solid
tumors, going from stage I to stage IV.  Stage I would be a
very superficial tumor in the lining of the esophagus that's not
actually penetrated in to the muscular wall of the esophagus. 
At the other end of the spectrum, we have stage IV disease, and in
that situation the tumor has spread to distant sites in the body,
again, such as the liver, and then stage II and III disease, means
you may have a tumor that has invaded deeply into the wall of the
esophagus or has spread to the lymph nodes or lymph glands in the
region of the esophagus.Foss
At the time of diagnosis Jill, what percentage of patient's have
early stage versus advanced stage?Lacy
The majority of patient's present with either stage II or III
disease.Boffa
 What's unusual about esophageal cancer, is it relates to the
anatomy of the esophagus, it is a muscular tube, but the lining is
more like the layers of a cake and the esophageal cancer starts on
the inside, or the frosting of the cake, if you will.  What's
unusual about the esophagus is the lymph ducts, which allow the
cancer to spread, are actually very close to the inside, or very
close to the frosting to stick with that tasty analogy, which means
that a relatively early stage esophageal cancer has much readier
access to spread then say a colon cancer or breast cancer.  If
you compare stage per stage, esophageal cancer is a very difficult
cancer to manage because of that anatomic reason, it has an earlier
propensity to spread.Foss
So, it would be very rare to pick up a stage I case for
instance?Boffa
 Historically yes, but now we are doing screening programs. Once it
is established that you have Barrett's esophagus, if you are
followed, chances are you will be much more likely to be
 found to have an earlier cancer or even high-grade dysplasia then
the more symptom driven diagnosis, which tends to be the stage III
cancers.19:45 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3Chu              
 Dan, can you take us through some of the different treatment
options, in particular the surgical treatment options for this
disease.Boffa
 Esophageal cancer can be treated with chemotherapy, radiation and
surgery primarily.  We have other techniques, but if you had
to separate the treatment for esophageal cancer, there is treating
the tumor in the esophagus with local therapy, which means you are
trying to get rid of the tumor where it started, and there is
systemic therapy, which means you are treating the whole patient
for anything that may have spread; systemic therapy is
chemotherapy.  Local therapy can either be radiation where you
try to destroy the tumor by radiating the esophagus and neighboring
structures, and surgery is where you remove that part of the
esophagus and all of the tissue around it.  Esophageal cancer,
again because of where it is in the body and the extent of surgery
you have to do to restore the patient's ability to swallow
normally, is a difficult cancer to treat surgically.  It
involves a substantial operation.  We select our patients very
carefully because the risk of esophageal surgery is much higher
then say colon surgery or breast surgery.  At Yale, every
patient is evaluated individually, and if we think there is a risk
of them having cancer throughout their body, even if it's
microscopic and you can't see it, we give them chemotherapy. 
Most patients get treated with chemotherapy and radiation followed
by surgery, sort of a multimodality approach, and the thought
behind that is that we give patients everything we have because it
is a difficult cancer to control both where we see it and where we
don't.Foss
Jill, can you talk a little bit about the kinds of chemotherapy
that are used for esophageal cancer?Lacy
As Dan has alluded to, the management of esophageal cancer is
typically interdisciplinary; it involves the use of radiation,
chemotherapy and surgery. Chemotherapy has an important role to
play in the management of all stages of esophageal cancer with the
exception of stage I, which is typically handled with either
surgery or focal ablative therapies.  There are two major
scenarios where chemotherapy is important.  First, in a
situation where you have a patient and they do not appear to have
metastatic disease and the plan is to take them to surgery for
localized or regional disease, and there, as Dan mentioned, we use
chemotherapy in combination with radiation that's administered
prior to surgery.  This will reduce the size of the tumor and
hopefully eradicate any metastatic disease. This approach has been
shown to increase the cure rate overall compared to surgery
alone.  The most commonly used and established regimen that we
use with radiation is a two-drug regimen using older drugs,
cisplatin and 5-fluorouracil, and they appear to still be the best
regimen that we have.  We also use chemotherapy, again in
combination with radiation, in a patient who may not have
metastatic disease but is not a candidate for surgery because of
medical problems that would23:26 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3
 make the risk of surgery too great. In that situation we know that
chemotherapy, again when given with radiation therapy, concurrently
not only can shrink the tumor substantially and improve symptoms,
but also in about 20% of the patients it actually appears to be
curative in the long run.Chu
Jill, is there ever any role for giving chemotherapy after the
surgical procedure has been performed to remove the esophageal
cancer?Lacy
Yes, there are some situations where going in to surgery all of the
staging studies would support an early stage esophageal cancer, say
stage I, and then once the esophagus and all the lymph nodes are
removed we find that the stage is actually higher than that, stage
II or III, and that's a situation where we know the patient is at
significant risk for recurrent disease and we certainly would
consider using either chemotherapy alone, or in some cases,
depending on the location, chemotherapy and radiation therapy in
hopes of reducing the risks.Foss
Jill, what is the role of some of the newer biological therapies
such as bevacizumab, which is the anti-angiogenesis antibody in the
treatment of esophageal cancer?Lacy
Unfortunately, more than 50% of patients with esophagus cancer,
even best case scenario, will have a recurrence or will present
with metastatic disease. In that setting, we don't, at the present
moment, have definitive curative treatments.  We know that
chemotherapy has an important role to play here; chemotherapy can
often dramatically shrink the tumor, thereby improving symptoms
such as difficulty swallowing and improved quality of life and can
also significantly extend survival.  But chemotherapy over
many decades has not been proven to be curative in this
situation.  So certainly we are searching and looking for
better therapies and there is tremendous interest in these new so
called targeted or biologic therapies, and one such targeted
therapy that looks very promising for adenocarcinoma of the
esophagus is Avastin or bevacizumab. This is a targeted therapy
that's received a lot of media attention.  It is a blood
vessel formation inhibitor, so we think it may work by blocking
blood supply to tumors, and it's already been approved by the FDA
for common cancers such as colon, breast, lung, and just last week
in malignant brain tumors.  We think that it may also be an
active agent in adenocarcinomas of the esophagus.  We have an
ongoing study here at Yale using Avastin, or bevacizumab, in
combination with the chemotherapy regimen in patients with
adenocarcinoma of the esophagus, and also stomach, who have either
recurrent disease after initial definitive treatment or present
with metastatic disease.Chu
Great.  Dan, over the last few years there has been an
increased use of giving chemotherapy before surgery, and I'm just
curious, from your perspective as a surgeon, have you noticed26:47 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-05-09.mp3
 any increased complications resulting from chemotherapy
beforehand, or have you found it to be much more helpful in
allowing you to get in there and surgically remove the tumor?Boffa
 Well, it's a very big operation and I can say that the
chemotherapy or radiation beforehand doesn't seem to significantly
alter the chances of having a complication.  Now that being
said, complications are common after esophagectomy and
complications that are well managed don't really affect the
long-term outcome.  What the centers that do esophagectomies
with frequency have over centers that don't is their ability to
identify complications and manage them safely so that the overall
result is very good. Centers like Yale that see a lot of esophageal
cancer and do a lot of esophageal operations have a real advantage
over centers that don't and are able to conduct these elaborate
procedures very safely.Foss
We talk about multimodality care for many cancers and both of you
alluded to the multimodality approach for esophageal cancer. 
For most patients who present with this, how did they enter this
system?  How did they hook up with multimodality care?Boffa
 As it's set up right now, if any of the members of the
multidisciplinary team, be it Harry Aslanian through
gastroenterology, Jill, or myself, once you are referred to any
member of the esophageal cancer team you become cared for by the
team. You still are cared for by the physician that referred you,
but you are discussed at the tumor board and we come up with a
consensus care plan to move forward.Chu
Great, well Jill and Dan thanks so much for being with us on the
show this evening. We look forward to having you back on a future
show to hear the latest about what's going on in the treatment of
esophageal and gastroesophageal cancer.  You have been
listening to Yale Cancer Center Answers and we would like to thank
our guests, Dr. Dan Buffa and Dr. Jill Lacy for joining us this
evening.  Until next time, I am Ed Chu from the 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.