Cancer Answers: Ovarian Cancer Awareness and Detection, September 14, 2008

Dr. Thomas Rutherford, Ovarian Cancer Awareness and
Detection September 14, 2008Welcome to Yale Cancer Center Answers with Drs. Ed Chu and
Ken Miller.  I am Bruce Barber.  Dr. Chu is Deputy
Director and Chief of Medical Oncology at Yale Cancer Center and
Dr. Miller is a medical oncologist specializing in pain and
palliative care and he also serves as the Director of the
Connecticut Challenge Survivorship Clinic.  If you would like
to join the discussion, you can contact the doctors directly at canceranswers@yale.edu or
1-888-234-4YCC.  This evening we welcome Dr. Tom
Rutherford.  Dr. Rutherford is the Chief of Gynecologic
Oncology and Associate Professor of Obstetrics, Gynecology, and
Reproductive Sciences, at Yale School of Medicine. He joins Ken
Miller to talk about ovarian cancer.Miller
Firstly, what is ovarian cancer and are there different types?Rutherford
There are many different types of ovarian cancer.  Basically,
it is a disease of the ovary.  It can be seen in the young,
such as teenagers. The earliest recorded age is 8, and it can be
seen in women up until the age of about 30-35 where you then start
seeing what is called a germ-line ovarian cancer.  These are
tumors that grow very fast and they grow in the ovary.  Young
ladies often look pregnant within a couple of weeks.  If you
developed one of these tumors prior to 1970, they were fatal. 
Today it is very rare to have a lady die of this disease.  It
does require surgery, where the ovary is removed and the affected
tissue as well, but it is a conservative surgery so the patient
should be able to go on and have children. It also requires
chemotherapy.Miller
Is germ-line the most common type?Rutherford
For children it is. 
                                                               Miller                 
 In my personal life, I have a neighbor whose daughter was 14 when
she developed an ovarian cancer, but is that different?Rutherford
That would be a germ-line tumor.Miller
It sounds like you are saying it is a very curable disease.Rutherford
It is curable and is very rare.Miller
Thank God.  I also wanted to ask you, before we start talking
about the most common type, there is something called a tumor of
low malignant potential, what does that mean?Rutherford
It is a cancer and there are different types of it. Basically it is
a surgical exercise.  That is a tumor that does not
show a lot of invasion into the basement membranes of the cells,
however, it also does not respond to chemotherapy.  So, it is
the surgical exercise to take the tumor out.  The tumor can
recur and it can have what is2:34 into mp3 file 
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 called micro-metastatic ability where the patient could get into
trouble, but most of the time they are localized within the ovaries
and you can surgically remove them.Miller
When you go to operate on a patient do you know what kind of cancer
or tumor you are dealing with?Rutherford
The only differential you are going to have is where the age
breaks; if you have somebody 35-40, or 35 or less, that is probably
going to be a germ-cell tumor.  If they are 40 or over, then
you start thinking that is the epithelial tumor, and that is the
most common tumor that we encounter.Miller
Because a lot of these women that you are mentioning are around 35
or 40, childbearing age, are there situations where you can
preserve fertility for women with various types of cancer?Rutherford
Yes, there are.  We have younger women, aged 30-35 every now
and then, with this epithelial tumor. If it is localized within an
ovary, we will take that ovary out, maintain the uterus and the
other ovary, and many times treat them with chemotherapy and
observe from that point.Miller
What is the most common type of ovarian cancer, and what is a
typical way that a woman presents to the doctor?Rutherford
The most common is the epithelial tumor where we think, Gilda
Radner.  These tumors often are present for up to 2 years
before we diagnose them, and the problem with ovarian cancer is
that it is a disease that whispers. You might go out to dinner and
have some spaghetti sauce and your stomach is upset, but it goes
away in a day or 2, and a couple of weeks later you have a little
symptom while you are working out at the gym, and that goes on for
6 months to a year. Then when they finally examine you they do not
see anything.  About 5 to 6 weeks before the patient comes to
us they have a lot of abdominal bloating, decreased appetite,
change in their bowel or their bladder function, and at that point
it is obvious that something is going on, but unfortunately, this
tumor is very indolent and very quiet. It is there, it is giving
you signs, but it is a backward-looking at it when you figure it
out.Miller
With those symptoms I wonder about when a woman eventually finds
out she has ovarian cancer, besides obviously being worried and
scared, are they upset, angry at themselves or doctors, what is the
feeling?Rutherford
Many times these patients have seen 3 or 4 physicians before they
come to us.  They are very disappointed in the medical system
for not identifying these tumors upfront.  They are
disappointed that they did not act more proactively, but the real
problem is that a lot of times you see the patient and the ovaries
are normal, they5:19 into mp3 file 
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 are small and are not becoming enlarged, yet they have this
disease. We have operated on people laparoscopically with symptoms
and you look and see nothing. You take the ovary out, or a piece of
what is called the omentum, and you find disease in the omentum. A
lot of this is microscopic that in the early stages you are not
going see.Miller
Even with the best technology, experts like you are self-examining
women and everything looks okay.Rutherford
We've been fooled.Miller
With men we are able to have a PSA drawn and have our prostate
examined and that is how prostate cancer is being found
early.  What progress has been made in terms of finding
ovarian cancer?Rutherford
In the past, the CA-125 was the big test.  The CA-125 and the
ultrasound is basically what we had for screening and neither one
of them really improved detection, but every now and then you got
lucky. However, in the laboratory we have been playing with a test
that looks at 6 different protein markers, and this is currently
being marketed by LabCorp. It is a serum test and it is being
looked at for women who have a family history or suspicion for
ovarian cancer, and hopefully this will help in detection. 
There is some controversy about it and it needs to be put through a
big pilot study because we need a large number of people to see how
well it is really going to do, but so far the test has been holding
up relatively well. We are able to identify some people with very
early ovarian cancer. It is not 100%, none of them are, but we are
going to have to wait a little while for the numbers.Miller
It sounds like, eventually, there may be a way to do a blood test
and test it early, but we are not quite there. Who would you want
to screen really carefully and how would you screen them right
now?Rutherford
We always talk about the BRCA1 and BRCA2 population, the Ashkenazi
Jewish population, and that helps.  If you are from that
linage, and you have a family history of a BRCA1 or BRCA2 positive
disease, that is fine.  In my family history, I have two
uncles with pancreatic cancer, I have an aunt with breast cancer,
and two aunts with ovarian cancer; all BRCA1 and BRCA2 negative,
all on my mother's side.  It does not have to be your mother's
side.  It could be from your father's side as well. 
Basically the tumors that ride together and increase your risk are;
ovarian, breast, uterine, colon, prostate, and pancreatic.  If
you have a BRCA1 and BRCA2 defect, that helps, because now we can
go and screen the rest of the family and if they also have the
defect then they are at a higher risk of developing one of those
tumors. If they do not have a defect or deletion, then you have the
problem.  We are playing in the laboratory with an entity
called microRNA. MicroRNAs are little8:30 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Sept-14-08.mp3RNAs.  It is a little different because it is not used in
transcription or in translation into protein.  It helps
regulate the cell and we have found that some of the RNAs, these
microRNAs are missing in patients with ovarian cancer.Miller
We are talking about microRNA. For the listening audience, and for
me too, tell us again what microRNA is. What does it look like,
what does it do?Rutherford
They are short fragments of RNA and they help regulate the cellular
function of how the genes work.  There are only about 480 or
so of these little microRNAs in the body that we have detected so
far.  They seem to be able to be identified in tumors as a
deletion, or a single nucleotide polymorphism, or SNP, and we have
been able to identify some of these abnormalities in ovarian cancer
and they are very specific which is interesting.Miller
Assuming that we looked at these patient's cells, the other cells
in the body, does that tell us something about them, or something
about the tumor?Rutherford
We can use what is called a buccal smear on the inside of the
mouth, and from the swab we are able to identify if you have that
deletion.  This is relatively new and is probably one of the
hottest topics in science at the current time. Most of what is
being published just came out over the last 18 to 24 months or
so.Miller
If you know someone at high risk based on family history, genetics,
or eventually let us say, based on microRNA, what would constitute
topnotch screening for them?Rutherford
One, we would use the Ova-Sure blood test from LabCorp. We would
use the ultrasound and we would use the CA-125.  Once we get
the population figured out on the microRNA, we have a specific
deletion that we know, and probably we would start looking into
that as a screening program as well.  There is no one test
that is going to do it, and even with the best of technologies, we
are still probably going to miss something.  The question
comes down to, how do we manage that risk?Miller
Who would you recommend for surgery and to have the ovaries
removed?Rutherford
What you want to do is look at where the family history is. 
The prophylactic surgery, we prefer to do around age 35.  With
the removal of the ovaries you decrease the risk of an ovarian
cancer and the risk of a breast cancer, but you do not decrease the
risk of ovarian cancer to zero. There is an entity called a primary
peritoneal cancer which can occur even if you remove the ovaries,
and it is just like an ovarian cancer because it is the same lining
inside abdomen as it is out of the ovary. The problem is that when
an ovary releases an egg during normal ovulation, a portion of the
surface of the ovary ruptures and it spreads through the abdomen.
That in and of itself can cause little implants later if a tumor
develops.  There are11:46 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Sept-14-08.mp3two ways to reduce the risk.  One is birth control pills,
and that seems to be very effective and we would want to put
somebody on birth control very, very early. You do that to prevent
ovulation, because we believe that the tumor is being caused by
inflammation, so during an ovulation cycle if you rupture the
surface of the ovary it undergoes a repair mechanism and
inflammation occurs that we believe has some impact on malignancy.
Where the theory falls apart a little bit is the other way to
reduce the risk of ovarian cancer is by tubal ligation. That also
decreases your risk of breast cancer.  Tubal ligation has
nothing to do with ovulation.  It interrupts the tube and the
blood supplies going to the tubes, so the question comes down to,
how does tubal ligation decrease the risk?Miller
What is the answer?Rutherford
We do not know.Miller
Alright, let us take a break. When we come back we are going to
talk more about ovarian cancer.  You are listening to Yale
Cancer Answers with Dr. Tom Rutherford, Director of the Gynecologic
Oncology at Yale Cancer Center.Miller
This is Dr. Ken Miller and I am here with Dr. Tom Rutherford who is
Director of Gynecologic Oncology at Yale Cancer Center. We would
like to remind you that you can e-mail questions to Yale Cancer
Answers by sending them to canceranswer@yale.edu. Tom, I did
not know about your family history, what led you into gynecologic
oncology? Was it related to that?Rutherford
Actually it was not.Miller
Okay.14:21 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Sept-14-08.mp3Rutherford 
         
 I did a PhD in molecular genetics and I was looking at an enzyme
called glycosol transferase. We were looking at leukemia and I
worked with a gentleman out in Toledo, Ohio who was a gynecologic
oncologist. He was working on a young lady who had ovarian cancer
and at that time subtraction hybridization was the big
technique.  I thought it would be as easy as, this is a normal
ovary, this is an abnormal ovary, I should be able to figure this
out. I was a little naïve. And that's what got me
interested.Miller
That is interesting, and I have to say, it is like that with all of
us. Sometimes it is one patient or one mentor that we have. 
How is ovarian cancer treated?Rutherford
It really depends upon the stage.  In early stage, we treat it
predominantly with surgery, plus or minus chemotherapy. Anything
beyond the early stage usually requires surgery and chemotherapy.
The question is, which do you do first?  With any tumor, there
are basically four stages. Stage I is confined to the organ. 
Stage IV means it is metastastatic, somewhere distant.  Stage
II is metastatic to whatever organs are closest and stage III is a
little farther wide. That is pretty much true for any tumor. 
So, stage I ovarian cancer is located within an ovary and is what
is called a well-differentiated tumor; the surface is not involved.
We would take the ovary out, do a hysterectomy, and remove the
lymph nodes along the major vessels in the abdomen and
pelvis.  There is also a fat pad that hangs off the stomach
called the omentum, we would remove that as well.  If just the
ovary is involved, we would stop.  We would just treat the
patient with surgery and she would not need chemotherapy. 
However, if it is a high-grade tumor, meaning a poorly
differentiated tumor, we would then go on and treat the patient
with chemotherapy.Miller
Of all the patients you see, or in gynecologic oncology in general,
what percentage have these very early tumors that are well
differentiated?Rutherford
Unfortunately, very few; probably 10 to 15%.Miller
In those women it sounds like many of them are cured
surgically.Rutherford
That is correct.Miller
And for women who do not fit that criteria, maybe stage I or stage
II but the tumor looks a little wilder underneath the microscope,
what would be the sequence of events for them?Rutherford
The lady would still undergo the surgery.  You do the
hysterectomy, do the lymph nodes, the omentum, remove any tumor you
see, and then the patient would receive chemotherapy.  The
chemotherapy we are using today is a platinum taxane base, plus or
minus a drug called Avastin which affects the vasculature to the
tumor.  It looks like Avastin is going to be moved up into the
front line.  It has a major17:13 into mp3 file 
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 advantage for the patients and there are several clinical trials
being run currently in the nation. One is being run by a
Gynecologic Oncology group looking at Avastin in advanced stage
disease. A second one is run by Genentech on recurrent disease that
they are bringing in as a second line therapy. Both of these trials
are showing that there seems to be some advantage to moving these
drugs up and I think in the future, you are going to see platinum,
taxane and Avastin or an Avastin like compound.Miller
Might that be the case even for women with early tumors?Rutherford
I think it is going to be.  If you can improve your advanced
stage, you want to improve your early stage, but even in early
stage there is a 20% recurrence rate.Miller
In other parts of oncology the same thing is happening.  In
terms of lung cancer treatment and colon cancer treatment, Avastin
is a very exiting drug. There is another approach being used in
other types of cancer where you treat someone upfront by using
chemotherapy first.  When might that be useful in your
field?Rutherford
Neoadjuvant chemotherapy was started with Peter Schwartz and when I
came here in 1993 I saw a lady with a very advanced cancer and he
asked me what we should do and I said, we go to the OR, and he
promptly told me I was wrong.  We treated her with
chemotherapy and then we went to the OR.  When a lady comes in
with advanced tumors or advanced stage disease, she has abdominal
bloating, a lot of fluid in the abdomen, and a lot of times they
can have fluid in their lungs and when you take them to the OR all
the tissue is soggy.  It is like putting her hands in a
dishwasher for a week.  Therefore, you have increased
bleeding.  The patient would often end up in intensive care
for prolonged periods of time and depending on who you want to
believe, somewhere between 60% to 80% of the time you can debulk
the patient to no residual disease, and that is in the best of
hands. You can get trials to show any number you want, but the
patient ultimately has a pretty rocky course.  They can
re-accumulate the fluid in the abdomen postsurgically and you're
always chasing them in the intensive care and they are pretty
sick.  The other thing that is true is that with the advanced
stage disease the patient has not been eating all that well so
approaching status is very poor.  If I can get that patient to
eat, we build her protein status, get rid of fluid, decrease the
volume of the tumor that would decrease my operative time and that
would make her recover faster postoperatively and reduce blood
loss.  So, we treat him with chemotherapy upfront and what we
have been able to show over the last 15 years is that if you have a
stage IV tumor in a patient, the proper way to treat that patient
is to treat that patient with chemotherapy upfront because we have
increased survival. If it is a stage III, meaning it is bad, but it
is not the worst, if you can debulk that tumor, and we can use CAT
scan criteria to determine that, that's fine and you treat them
with chemotherapy.  If you cannot debulk the tumor to no
residual disease, which is what we are looking to do20:24 into mp3 file 
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 anytime we go to the OR, remove all tumor, then that patient
should probably be treated with chemotherapy upfront followed by
surgery.Miller
When we talk to women about using chemotherapy upfront instead of
operating, and we have these discussions in breast cancer as well,
what do women typically say to you, what concerns do they have?Rutherford
For ovarian cancer, if you asked this 10 years ago, the standard of
care was to treat the patient with surgery followed by
chemotherapy.  Gynecologic oncologists do not always do the
chemotherapy; a lot of times we send the patient into medical
oncology, like they do at Memorial Sloan-Kettering, they have a
split division on who is doing what.  If you go and see the
gynecologic oncologist he is going to tell you that you need an
operation, in fact, that is what they push. The question is, is
this the right thing to do?  When you look at recovery time,
how the patient does long term is what really drives it.  We
have a frank discussion of how well our patients do and how long,
or short, they are going to be in the hospital for and what the
postoperative recovery time is.Miller
You were saying that it looks like survival may be better in those
patients who get preoperative therapy.  Is that because the
postoperative course is easier, or do you think it really gets rid
of more cancer cells?Rutherford
We have a theory.  In the laboratory, under Gil Mor, we have
been able to identify what we call the stem cell.  That stem
cell was chemo resistant.  So, when you treat an ovarian
cancer, the biggest problem you have is that over time that disease
comes back.  We can get to no residual disease, and it can
stay dormant for a couple of years and then, unfortunately, many
times it comes back.  The cell that is coming back is what we
believe to be the stem cell, a chemo resistant cell.  If I
treat a patient with chemotherapy, I kill all the soldier cells,
leave the chemo-resistant cells behind and at the time of surgery,
we can remove it.  I think that might be what is
happening.Miller
In your department, you and Gil Mor in particular, have been
leaders with other members like Dr. Schwartz in terms of treating
women with chemo resistant ovarian cancer. Can you tell us a little
bit about some of the work that you are doing?Rutherford
We have looked in the past into a drug called phenoxidiol. 
What happens with chemotherapy is that it works for a while and
then it stops working.  So, the question is, does the cell
figure out how not to undergo self-death called apoptosis, or can
we modulate that mechanism to make it reactivate? We came up with a
drug in the laboratory called phenoxidiol and we found that if you
use that in the laboratory, and even in the clinical trials, it
seems to have an effect on chemo23:25 into mp3 file 
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 resistant reversal. We went from a phase I, II clinical trial, and
currently we are on a multinational trial, phase III, looking at
phenoxidiol in combination with chemotherapy to see if we can
reverse the resistance, and so far, we have had some encouraging
results.Miller
Just looking back in the last 10 years, the combination you are
talking about, Taxol or the taxane and the platinum drug,
have been used for quite a while. Are there any other drugs proven
to be useful that may take the place of these other two?Rutherford
What we are going to see is biologic modifiers being used, and I
think that is where the push is going to come from. There are a lot
of different trials currently that everyone is looking at.  I
do not think anybody has anything that they can say, this is going
to be the next drug that we are going to use.  There are other
drugs we have looked at such as topotecana and gemcitabine. 
Doxil is a very nice drug in the sense that it has been repackaged
from Adriamycin so that you do not have the cardiotoxicities. In
fact, we have gone back and have started to use a drug called
Alkeran which everybody is surprised on line 13 or 14 works.Miller
It sounds like there are also a large number of women who are
living with cancer.Rutherford
Correct, we have many people that we treat off and on with
chemotherapy.  I have patients out anywhere from 8 to 15 years
that receive chemotherapy off and on.Miller
And they are leading a relatively good life?Rutherford
A very good life.  Quality of life is very important.Miller
What other clinical trials are you involved in, in your
department?Rutherford
We are members of the Gynecologic Oncology Group which is a
multinational group of GYN oncologists.  There are multiple
trials going on right now. We have a lot of phase III and some
phase I and II to see which drug combination seems to have the best
effect.  We also do a lot of industrial trials.  We work
with Genentech and GlaxoSmithKline. We have a series of trials that
are in design because we think we knock out that stem cell by
playing with one of the receptors between cell membranes, and if
that holds true, that is going to be a real breakthrough.  It
works in the animal model so if we get it to work in a person, I
think we got this one.Miller
One of the things I am impressed with is that at the start of my
career a lot of times surgeons would say, I got at all, and a lot
of diseases like breast cancer are treated very much surgically,
but it sounds like what you are talking about is a collaborative
effort.26:19 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Sept-14-08.mp3Rutherford
Oh, absolutely.  What happens is that when that ovary ovulates
and that cell ruptures it's like rupturing a balloon; it just
bursts through the abdomen.  When we say, we got it all, that
means we took out everything we could see. The problem is what we
cannot see. We have all taken out an ovary or a piece of tissue
that looks totally normally, put it under the microscope and it is
completely malignant.Miller
So ultimately it is really a matter of, you remove as much as you
can to your vision and touch and then the rest is using
chemotherapy and some of these newer agents.Rutherford
Correct.Miller
Has the prognosis for women with ovarian cancer improved since the
start of your career?Rutherford
The actual cure rate may not have improved all that much, but it
has improved a little.  What we are definitely seeing is that
women are living much longer with the disease and have a functional
life. It is closer to diabetes; we cannot cure diabetes.Miller
Correct.Rutherford
But people are living longer and more functional lives with it.Miller
Wrapping up, let me just ask you, how do women avail themselves of
being involved in clinical trials, at Yale or elsewhere?Rutherford
I would encourage people to participate in these trails. The only
way to get Avastin today for ovarian cancer is in a clinical
trial.  We know that the drug has activity, and some people
will say, I do not want to be the guinea pig, but you want to be
the guinea pig for this trial. I am not saying you do for all
trials, but sit down and talk with you physician about this
one.  I think most physicians are going to be very honest with
you and say that they would do this trial if they were you, or if
it was a family member.  A lot of the trails we are doing
today are bringing you the drugs that I cannot get you any other
way.Miller
There is very careful monitoring on clinical trials and the other
gift the patients are giving is knowledge to science and to
medicines, so that hopefully other women will benefit along with
them.Rutherford
That is correct.Miller
Tom, I want to thank you for joining us.  It has been a very,
very interesting session as it always is when you come.  Until
next week, this is Dr. Ken Miller from Yale Cancer Center wishing
you a safe and healthy week.28:49 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_Sept-14-08.mp3If you have questions, comments, or would like to subscribe to
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where you will also find transcripts of past broadcasts in written
form.  Next week, Dr. Francine Foss talks to Dr. Ken Miller
about the latest developments in the treatment of lymphoma.  I
am Bruce Barber, and you are listening to the WNPR Health Forum
from Connecticut Public Radio.