Dr. Robert Mayer, Systemic Therapies for Colorectal
Cancer
May 9, 2010
Welcome to Yale Cancer Center Answers with Dr. Ed Chu and Dr. Francine Foss, I am Bruce Barber. Dr. Chu is Deputy Director and Chief of Medical Oncology at Yale Cancer Center and Dr. Foss is a Professor of Medical Oncology and Dermatology specializing in the treatment of lymphomas. If you would like to join the conversation, you can contact the doctors directly. The address is canceranswers@yale.edu andthe phone number is 1888-234-4YCC. This evening Francine welcomes Dr. Robert Mayer. Dr. Mayer is the Stephen B. Kay Family Professor of Medicine at Dana-Farber Cancer Institute at the Harvard School of Medicine. Here is Francine Foss.
Foss
Let's start off by talking a little bit about your interest in
colon cancer, can you tell us how long you have been interested in
colon cancer?
Mayer
When I was a medical student years ago, I was undecided whether to
become a gastroenterologist or to become a cancer doctor. I
always thought that the diseases of the bowel and nutrition and how
food is absorbed, or not absorbed, was fascinating, and then when I
learned about the cancers that were associated with it and the
progress that could be made and also the needs of our patients,
putting the two together seemed like a great idea and I have been
doing this in large part since 1974.
Foss
Bob, colon cancer is one of the most common cancers in the United
States, can you talk a little about the incidence of colon
cancer.
Mayer
There will be close to 150,000 new cases of colon cancer this year
and that will lead to about 49,000 deaths. The 49,000 deaths
reflect the second most common cause of cancer death in the United
States among all the cancers we deal with; that's the bad news. The
good news is that the number of 49,000 is down from a level of
about 60,000 20 years ago. So it's somewhere in the range of
a 13% decrease in colon cancer deaths that have occurred right in
front of our eyes.
Foss
Can you talk a little bit about why that might be? We have all
heard the word screening and we use screening in many types of
cancers, but this may be one instance where screening has really
made a difference.
Mayer
It certainly has. Screening is very important in cervical
cancer, it's very important in breast cancer, but there is no
disease in which it is as effective as in colon cancer. The reason
for that is that the cancers don't just develop out of the clear
blue, rather, in the lining of the bowel, benign growths called
polyps appear. Polyps occur in about half of Americans by the
time they are at the age of social security, 65 or 70, and as a
generality about 90% of colon cancers emerge from polyps.
Many people think that going from a normal bowel, to a polyp, to a
cancer occurs in a few weeks or a few months, maybe a year.
It actually takes
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somewhere in the range of five to six years and it has become
clear that removing these polyps prevents cancers from occurring,
and as a result, the removal of polyps, so called polypectomies,
that are performed at the time of a colonoscopy represents the
single most effective means of primary prevention of colon
cancer.
Foss
In terms of our recommendations now for screening for colon cancer,
could you go over those with us?
Mayer
Years ago, the most common test that was used was checking the
stool for the occult presence of blood. This turned out to be
an effective but not sufficiently effective approach because many
times cancers don't bleed and looking for blood in the stool is a
surrogate means, if you will, for finding a cancer or even a
bleeding polyp, and also, the vast majority of times that blood was
found in the stool it was falsely positive. As a result,
people have looked for other tests. One intriguing
test is actually an experimental approach of
taking stool and extracting the genetic material from it, so called
DNA, and looking for mutations that might be present which are
often present in a colon cancer or a polyp, that probably isn't
ready for primetime. Sigmoidoscopy, which means inserting a
tube into the lower part of the bowel, has about a 75% accuracy
rate meaning that the majority of cancers do occur on the left side
of the colon, which a sigmoidoscope can reach, but it isn't100%. So
the two tests right now that are the most intriguing are a
colonoscopy where a small tube is inserted through the entire large
bowel from the anus to the appendix area in the right side of the
colon looking not just for cancers, but for polyps and removing
them. An x-ray test called a virtual colonography, sort of a CT
test of the bowel, is not quite as accurate as a colonoscopy, it
doesn't find every polyp, but it certainly avoids the need for
being impaled, if you will, by a tube that goes through ones back
side. However, both of those tests, the colonoscopy and
virtual colonography, require cathartics because the bowel has to
be sufficiently cleaned out, and at the present time, the
colonoscopy is the preferred test because it is not just
diagnostic, meaning you find an abnormality, but at the very time
you find the abnormality you can biopsy it, or remove it, so it's
both diagnostic and therapeutic. Nowadays, it's been
recommended that for people who have no history of polyps and no
family history of colon cancer, which is most of us in this
country, we start to perform a colonoscopy at about age 50. The
reason age 50 is chosen is the colon cancer usually occurs in
people in their mid 60s, so doing it any earlier is probably doing
too much testing, doing it any later might be missing some early
lesions that could be identified and removed or cured. The
notion has been put forth that if you have a completely negative
colonoscopy and you don't have a family history, you probably need
the test to be repeated only once every ten years, and maybe in
your whole lifetime you will have it done two or three times and if
it remains negative, you simply aren't going to make polyps and
that's all the testing you need. Whereas, if you do find
polyps, meaning you are one of the 50% of Americans who are polyp
producers and
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have these pre-malignant growths in the bowel and they are removed, the colonoscopic examination should be repeated every three to four years. So having it done at about age 50 and then maybe at age 60 is a dividing path between a high risk and standard risk individual and determines how often screening should be performed.
Foss
Would you say that having a colonoscopy over age 50 is probably the
most important thing that the average adult can do to prevent
cancer?
Mayer
It certainly is the most important diagnostic or screening
study. There are ways that all of us can prevent the polyps
from occurring. The colonoscopy is there to identify the
polyps once they appear. Folks who have a diet very high in
red meat, folks who are obese, and people who smoke a great deal,
those are all people that have a greater likelihood of developing
polyps and secondarily, developing cancer. There are things
that we can do in our own lifestyle. There are some rather
strong hints that utilizing Aspirin, one Aspirin tablet each day,
is not only helpful in protecting the coronary arteries from having
a heart attack, but also may prevent polyps from occurring.
There are data just emerging that perhaps having a little bit more
vitamin D in ones diet could be useful as well. So, there are
added lifestyle efforts that one can incorporate into our
day-to-day existence that will diminish the polyp risk and the
cancer risk as well.
Foss
When you talk about risk factors for colon cancer, we have talked
about a couple of things, but could you go into a little more
detail about other risk factors, for instance, are there familial
cases of colon cancer? Are there specific genes associated with
colon cancer that we should know about?
Mayer
Yes, somewhere in the range of 15% to 25% of colon cancers occur in
individuals who's families or members of their family also have or
have had a colon cancer in the past. We really only
understand the molecular genetics, the reasoning behind them
developing this condition in maybe 5% to 6% of that 15% to 25%
group, so maybe about a third or a quarter of that group.
There are two syndromes that one quotes quite often, 1% of colon
cancer occurs in families in which by about age 20, thousands of
polyps cover the entire large bowel, and that's something called
familial polyposis. It is conveyed through families by what
is known as an autosomal dominant, which means it is very commonly
spread from one member of the family to the next generation and
essentially everybody who develops this condition, the polyps
throughout the large bowel, will develop a colon cancer generally
by about age 35 to 40; now that's the bad news. The good news
for this is that there is a blood test that can identify the
carriers of this gene, even when they are teenagers before polyps
have developed by something called the familial adenomatous polyp,
or adenomatous
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polyposis gene, located on one of our chromosomes, chromosome 5,
and in people who have this carrier condition, in early adulthood,
around age 20, a prophylactic operation can be performed to remove
a good part of the large bowel. In the past, that required
the construction of a bag, a permanent colostomy where fecal
material would come through the abdominal wall, but there are now
ways to do that through ones back-side and avoid that and greatly
reduce the cancer risk. Sometimes people with this uncommon
syndrome also have other associated findings, which range from bone
cysts to malignancies in the small bowel to pigmentation in the
retina, but certainly in folks who have this condition prompt
referral to a genetic counselor would certainly be
mandated.
The other major genetic syndrome has a lot of words associated
with it, it's called hereditary nonpolyposis colon cancer and it
was described by a gastroenterologist and geneticist by the name of
Henry Lynch in Nebraska, and it is sometimes known
as Lynch syndrome. This is a condition in which people
develop colon cancer in their late 30's. The cancers
generally are found on the right side of the colon, meaning closer
to the appendix rather than at the part nearer to the anus.
People who have this condition, particularly women, are more likely
to have ovarian and uterine cancer in association with it and men
may have more prostate cancer. So those are the two genetic
syndromes that we know a great deal about, but taking a family
history, and if other members of ones family have developed colon
cancer, particularly before age 50, screening at an earlier age
should be undertaken.
Foss
This has been a really great discussion about screening and
prevention of colon cancer. We are going to take a break now
for a medical minute. Please stay tuned to learn more about
the therapies for colon cancer when we come back with our guest Dr.
Robert Mayer.
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Public Broadcasting Network.
Foss
Welcome back to Yale Cancer Center Answers. This is Dr.
Francine Foss and we are here today with my guest Dr. Robert Mayer
who joins us to discuss colon cancer. We talked a lot about
the epidemiology of colon cancer in the beginning of the show, but
at this point, if you are a patient say who has been diagnosed with
colon cancer, who has had a colonoscopy that's positive for colon
cancer, what are the next steps?
Mayer
Francine, the first step is to be certain that this is only a
single cancer, so one wants to be sure that a full colonoscopy has
been performed. After that, a CT scan of the chest, abdomen,
and pelvis is generally carried out because one wants to be certain
that there hasn't been any disease spread. If there has, God
forbid, been spread to the liver or the lungs, unless somebody is
quite symptomatic from the cancer one might want to think twice
about subjecting them to an operation. If the cancer is
located in the very far end of the colon in what's called the
rectum, one might want to consider giving patients chemotherapy and
radiation therapy before an operation. One really wants to
have their ducks in a row and know what's happening, draw blood
studies, but let's assume that nothing further is found. Then
I think it's very appropriate for that patient to be seen by a
surgeon who has experience in operating on cancers in general, and
gastrointestinal cancers in particular, and unless there is a
reason against it, an operation should be performed.
Foss
Bob, is this a disease that is approached from a multimodality
point of view at the very beginning?
Mayer
It may be and it really depends where the cancer is and it also
depends on what the extent of the disease is, the so called
stage. Furthermore, since many people with colon cancer tend
to be elderly and a big operation with an incision, the types of
operations that we think about where people have scars on the
abdominal cavity and a long time for recovery, that may be
something that is hard for a grandparent to successfully endure.
Now, with what we call noninvasive surgical approaches where there
is really no scar, but just probes placed into the abdomen, and
this is all done with very fine technique with just as much tissue
removed, and the results are just as good as the big traditional
operation, it's very important that a patient be seen by a surgeon
who is up-to-date and knowledgeable on contemporary techniques,
both to enhance the cure, potential for cure, and to diminish the
likelihood of side effects.
Foss
Now that we are doing colonoscopies on everybody over the age of
50, are we finding more disease at early stage?
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Mayer
Well we think that's probably why the number of cancer deaths are
dropping, but I think we are also finding polyps and removing the
polyps. Both of those factors come into play. Clearly,
if we find a cancer that has not invaded deeply into the wall of
the bowel or has not spread to the adjacent regional lymph nodes,
then the likelihood of cure with surgery alone is well over 80%,
and probably over 90%. If, on the other hand, the disease has
spread to the lymph nodes, and the only way one knows that for
certain is after the operation is performed, but if that turns out
to be the case, without further treatment, the likelihood of cure
is only 50% to 60%. That's the very setting where a medical
oncologist might recommend prophylactic, postoperative, or the
jargon that's used, adjuvant chemotherapy, for several months and
that approach has increased the likelihood for cure for these
people from the 50% to 60% range to about 70% to 72%, which is a
major step forward.
Foss
Could you clarify for our listeners, in patients who have had
surgically resected colon cancer, which of those patients requires
adjuvant therapy, and which of those patients will do well without
the additional chemotherapy?
Mayer
The first issue is, was the tumor from the rectum or was the tumor
from inside the abdominal sac, the peritoneum, that tissue that
wraps around the abdominal cavity, and when it gets infected, we
call it peritonitis. If it's in the rectum, which is deep in
the pelvis, we often offer radiation therapy and chemotherapy, even
if lymph nodes have not been involved. For the rest of the
abdomen, for most patients who have no evident spread of the tumor
to lymph nodes, we generally, but not always, think that surgery,
if it's a good operation with an adequate sampling of lymph nodes,
is all that a patient might need. Now that's not for everybody, but
for the majority of patients. Every patient with spread to a lymph
node or more, should be strongly considered as being a candidate
for receiving six months of prophylactic or adjuvant
chemotherapy.
Foss
Could you go through just briefly for us what the adjuvant therapy
entails?
Mayer
The adjuvant therapy now-a-days entails the administration of 3
drugs. One is a very traditional and older drug called 5-FU,
or the chemical name which is 5-fluorouracil. That's a drug that we
have had available for 50 years. The efficacy of that drug
has been enhanced when a vitamin or vitamin-like molecule similar
to folic acid, something called folinic acid or leucovorin, is
added. For many years 5-FU and leucovorin were the standard
adjuvant treatment given once a week, but more recently adding a
third drug called oxaliplatin seems to enhance the likelihood of
cure, and makes the treatment more effective. This
combination of drugs is usually given every two weeks for a total
of 12 treatments over six months. We are not certain that the
six months is chiseled in marble and there is soon to be an effort
throughout the United States to determine whether 12 weeks/3 months
is as good as 24
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weeks/6 months and my own suspicion is that less will be as good as more and that we will find the same very encouraging results with three months of therapy.
Foss
What are the side effects of this therapy? What will a patient
experience during the course of this treatment?
Mayer
The major side effect will be neuropathy. Neuropathy is a
fancy word that means pins and needles in the fingers and toes, and
why that is the most common side effect is because the other
possible toxicities that were associated with this treatment such
as nausea and vomiting, and low blood counts that could make
somebody prone for infection, can be controlled very nicely with
prophylactic medication. The ability to control cancer,
chemotherapy related nausea and vomiting, has grown and increased
and developed in a wonderful manner, so that patients now eat lunch
while they are getting their chemotherapy and don't even know what
the nausea and vomiting is about. The low blood counts can be
prevented in people who are prone to it with a stimulant to the
bone marrow, so the neuropathy which is pins and needles in the
fingers and toes is the major concern, as this develops somewhere
in the range of 40% to 50% of the patients. Within 6 to 9
months of the completion of treatment, it's resolved in three
quarters of patients, but there is still a small percentage, a
definite percentage of patients who have received this potentially
curable form of treatment, who have as a long-term reminder of that
treatment numbness in their feet when they walk and a loss of touch
sensation in their fingers, which makes working on a Word Processor
or perhaps playing the piano or some other tactile activity a bit
more difficult than it was before. So it's a matter of
balancing the potential risks and the potential benefits in the
sense of somebody who has a large number of lymph nodes involved in
colon cancer. There is no question that the benefits outweigh
the risks for one involved lymph node, it's a marginal decision and
that's something that I would very much encourage all our
listeners, if they are in that position, discussing openly with
their physician, their oncologist.
Foss
You have been involved and are at the forefront of a lot of this
research on the national level, and I think one of the major
advances in colon cancer has been this recognition that there is a
benefit to adjuvant therapy as you have said, even though there are
some downsides for the patient.
Mayer
Absolutely, I think there were two major steps forward. One
is better treatment in the adjuvant treatment, but I want to get
back to something we talked about earlier and that is the notion
that has now been embraced by the medical community and the public
in the United States, of the importance of screening. I especially
want to acknowledge the courage of Katie Couric who underwent a
colonoscopy on national television; some scientists, some
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epidemiologists showed that the frequency by which the American population underwent colonoscopy screening rose immediately thereafter. We have learned a lot more about what causes the disease, and there are lifestyle changes we can do to prevent it. We know that there are certain families that are more prone, and we have better screening tests and better ways to treat the disease. On the one hand, it's not surprising that the number of deaths have dropped by 13% or 14%. On the other hand, the challenge that we all have is to make certain that decrease in the number of deaths continues because there is every reason to think that the present 49,000 deaths a year from colon cancer can be reduced by at least another 50% in the near future.
Foss
What about those unfortunate individuals who have metastatic
disease, or who have relapse disease and don't respond to their
adjuvant therapy?
Mayer
Or people who were given the adjuvant therapy and their disease
recurred. There are alternative forms of treatment.
There are different forms of chemotherapy. There are the uses
of targeted, so called monoclonal antibodies, directed against the
formation of new blood vessels that feed tumors, particularly
metastatic tumors, tumors that have spread. There are
monoclonal antibodies that block sites on the cell, almost like
putting your auto- key into the ignition that when it's turned on
get the engine going, get the cells dividing, make the
cancer spread, there are ways of blocking that. The most common
site where colon cancer spreads is to the liver and there have now
been several reports where one can give chemotherapy to people with
spread to the liver, the liver spread shrinks, that area can be
surgically removed, and these people can be cured. On the
other hand, most people who have metastatic disease will eventually
succumb to their illness. In the past that mortality time
might have occurred within 6 to 12 months, now it occurs much
later, people live 24 or sometimes 36 months. Even in this
situation the life span can be prolonged and our challenge is to
identify newer and more affective treatments, fashioned directly
for a given patient's tumor by the biological characteristics of
the tumor, so as to enhance the cure to a greater extent than we
already have.
Foss
So personalized medicine is going to be applied and even is being
applied to colon cancer patients as we speak.
Mayer
Absolutely, there are blood and genetic tests that are called
biomarkers and these biomarkers are teaching us in the most
sophisticated manner in which patients the disease is going to act
badly, in which patients the disease is going to respond better to
treatment X versus treatment Y, which patients don't need any
treatment at all, and which patients might require some
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experimental form of therapy because standard therapy is unlikely to benefit them. This is a brave new world that has begun as the laboratory work of the last 20 years has really come to the clinic, to the doctor's office, to the bedside, but I really hope and expect that this progress is going to continue full force in the years to come.
Foss
It's really been terrific having you on the show tonight talking
about colon cancer therapies and it sounds like we could easily
have another whole show talking about some of these new
approaches. This is Dr. Francine Foss, until next week
wishing you a safe and healthy week.
If you have questions or would like to share your comments, visit 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 on the Connecticut Public Broadcasting Network.