The History of Chemotherapy

Dr. Vincent T. DeVita, Jr., The History of
Chemotherapy July 6 , 2008Welcome to Yale Cancer Center Answers with Dr. Ed Chu and
Dr. 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. 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.  The address
is canceranswers@yale.edu and
the phone number is 1-888-234-4YCC.  This evening, Ed Chu
welcomes Dr. Vincent DeVita, the Amy and Joseph Perella Professor
of Medicine at Yale University.  Dr. DeVita is also a former
Director of the National Cancer Institute and of Yale Cancer Center
and he joins Ed this evening to discuss the history of
chemotherapy.DeVita
Chemotherapy was first coined as a word by Paul Ehrlich, a chemist
who was well known in the early 1900s. He defined it as using
chemicals to treat syphilis.  His major contribution was that
he developed the rabbit model of human syphilis and developed a
series of compounds, one of which was compound 606 (Salvarsan),
which was used by medical professionals to treat syphilis. 
This was the birth of trying to find chemicals using animal models
as screens so that you could treat a disease. He had a wing in his
laboratory where he did the same kind of work trying to find
chemicals that might effectively treat cancer.  He had a sign
over the door that said "Give up all hope, you who enter."  So
he was not optimistic about the likelihood of finding chemicals
that would cure cancer, nor did he ever actually find one during
his lifetime.Chu
When was chemotherapy first developed and then applied to treat
patients with cancer?DeVita     
 There is an Egyptian papyrus that actually talks about using
topical chemicals, herbs, and extracts of herbs and so forth. 
So you can go as far back as you want, but it was really not until
around the mid 1930s that people began to think you could
realistically use chemicals for cancer. The first major screening
program was started in around 1935, but frankly, the date that
people use for the birth of chemotherapy is 1943, and it was here
at Yale. Based on experiences in World War I and then an accident
in World War II with mustard gas, data showed that people who died
had an atrophy of their bone marrow and their lymph nodes
disappeared. It was then thought that maybe they would be useful
chemicals for treating a group of diseases called lymphoma, or
cancers of the lymph nodes. Alfred Gilman, here at Yale, and Gustaf
Lindskog, who was a thoracic surgeon at that time, used an animal
model of lymphoma and screened these chemicals. They found that it
actually worked and so they convinced Dr. Lindskog, who had a
patient who was having trouble breathing because of a large tumor
mass in their neck, to let them test it. This was before the3:19into mp3 file 
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 FDA was involved in these things, and they got a
very dramatic response that started the whole interest in cancer
chemotherapy.  That paper was not published until 1946 because
of the secrecy of the war gas program, but it is generally regarded
as the beginning of human cancer chemotherapy.Chu
It is interesting, as you just commented that it came out of the
chemical warfare program that we had here in this country.DeVita
As a matter of fact, later in 1955, because of the interest in
nitrogen mustard another drug was developed called methotrexate,
which was also worked on here at Yale by Joe Bertino and people
like you in the lab.  The Cancer Chemotherapy National Service
Center was started on 1955, which was a national program to begin
to screen chemicals for cancer in a major way so that the birth of
chemotherapy here lead to development of a national screening
program.Chu
It is fascinating to me as I learn more about the history of cancer
chemotherapy having the privilege and honor of working closely with
you. The whole concept of cancer chemotherapy was not widely
embraced when these first discoveries and treatments of patients
with cancer came about.DeVita
You are being very polite, but no, it was not widely
embraced.  In fact, the critics were vitriolic about it. 
It was something about the self-fulfilling prophecy.  Cancer
is a fatal disease, if you do not treat it, it is indeed a fatal
disease.  People just did not believe you could ever cure
cancer with a drug. Nitrogen mustard worked, but it worked very
briefly. The people who were involved in developing nitrogen
mustard became harsh critics of cancer chemotherapy because they
were so disappointed after getting their hopes up that they were
going to finally have a drug that will cure cancer, that they never
believed that you could cure cancer with drugs. The original
pioneers are the people who started using chemotherapy. The
original pioneer would probably be Alfred Gellhorn who was Director
of a cancer center that was attached to Columbia University. People
like him were driven out of town. I interviewed him at age 94; last
November he passed away. I interviewed him in his office.  He
was working at age 94 and he told me about the great Robert Lurb
who was the chairman of medicine at Columbia. He was a great man, a
great teacher and a great academician.  He used to say to him
in front of people, "Alfred you are part of the lunatic
fringe."  The impact of having someone of his
stature say something like that, even if it
was partly in jest, is really enormous.  Eventually, he was
run out of town and the Hospital was closed because people did not
like the idea of cancer patients being treated and having6:34into mp3 file 
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  their house staff being exposed to this. There are many
other examples of that kind of thing happening.Chu
So what turned things around in the evolution of cancer
chemotherapy?DeVita
Well, as you know, you needed evidence that you could cure cancer
and that was provided by two diseases, childhood leukemia and
Hodgkin's disease.  More than one drug became available and
work was done in childhood leukemia combining several drugs, one of
which was the drug vincristine, which became available in the late
1950s. The first program that was developed and was quite
successful was called VAMP, the initials stand for the drugs in the
program, and that increased the remission rate in leukemia to about
50%. The striking thing was that these people now stayed in
remission for long periods of time.  By 1970, people were
saying you could cure childhood leukemia.  At the same time,
we were doing work on Hodgkin's disease and developed the MOPP
program. The complete remission rate went from virtually 0 to about
80%, and that is just the 40-year follow-up on that original study.
55% of the original groups of patients are alive 40 years later. By
1970 it was also apparent that Hodgkin's disease was very likely
cured by chemotherapy.  That provided the spark that had been
missing. Then what happened after that, which is a very important
thing, was that people went out willing to test drugs in the
postoperative period for patients whose tumor had been removed, but
we knew they would have a high risk of recurrence, particularly in
breast cancer and colorectal cancer, and so the early studies, and
what we now call adjuvant therapy, came right on the heels of that
adjuvant to surgery, and of course these studies have been
brilliantly positive.  The mortality rates from both
colorectal cancer and breast cancer are falling. At least 50% of
the decline in mortality is due to the application of chemotherapy
as an adjunct adjuvant therapy to surgery.  I think the big
impetus was what I call the concept of cure, that you could
actually cure cancer with drugs.Chu
The important concept was that combination chemotherapy was
essential to being able to cure cancer.DeVita
Indeed, and of course it was a dirty word in medicine at that time.
If you gave combinations of antibiotics, for example, you were
considered a sloppy practitioner.  Combination chemotherapy
was not something that was accepted at the time when I worked with
the two founders in this field. I watched them being criticized in
unbelievably vitriolic ways.  When I got to Yale, I used to
talk about their work and there was no acceptance of it at Yale
either, because it was just something that was not done.  The
important message, however, is that now that we have targeted9:31into mp3 file 
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  therapies, combination chemotherapy is still required.
Cancer is such a complex derangement that you need to target more
than one pathway.  In very rare exceptions, for example with
the disease chronic myocytic leukemia, it is treated with Gleevec.
It has one abnormality so you can treat the one abnormality. 
Take a cancer like cancer of the pancreas.  There are about 12
different key abnormalities and you are going to have to make
different kinds of combination chemotherapy, but the principle is
the same.Chu
As we are now seeing this era of targeted therapy, which perhaps we
can talk more about later in the show, is that it does look like we
need combinations of targeted therapies and combinations of
targeted therapies in combination with chemotherapy to perhaps have
the greatest effect on killing the tumor cells.DeVita
Yeah, absolutely, because what the targeted therapy does, that we
see now, is it resets. I do not know if the audience is aware of
the word apoptosis, but it means cell death, cell suicide.  We
have built-in mechanisms in our body for cells to commit suicide
when they are no longer functional.  For example, as an embryo
we have webs between our fingers, but we are not born with webs
between our fingers normally because these mechanisms make sure
that the cells that are not needed any longer die. Every cell on
the body has an apoptotic mechanism.  A lot of the targeted
therapies actually reset that mechanism so that when you damage it
with chemotherapy, the cells commit suicide.  So the
combination of the targeted therapy and chemotherapy is going to be
part of the future for combination chemotherapy.  The problem
we have with that is that all the regulations in the Food and Drug
Administration process are contrary to allowing you to do that kind
of thing. It is very difficult to develop these innovative
therapies today.  There is a study coming out very shortly
looking at the time it takes for a protocol to be approved, to go
through the process at a cancer center at the National Cancer
Institute and the FDA. If you want to guess, you will never get it
right on. It is 800 days.Chu
 Wow!  800 days.DeVita
 In some cases 1000 days, this means that the study that you are
starting that was written 800 or 1000 days ago, is out of
date.  We have a logistical problem that I am trying to solve,
how cancer cells grow and how can you kill them?Chu
 We would like to remind you to email your questions to12:09into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-06-08.mp3canceranswers@yale.edu,
or call on 1-888-234-4YCC.  At this time, we are
going to take a short break for a medical minute.  Please stay
tuned to learn more information about the history of cancer
chemotherapy with our special guest, Dr. Vincent DeVita, from the
Yale Cancer Center.Chu
 Welcome back to Yale Cancer Center Answers.  This is Dr. Ed
Chu and I am here in the studio this evening with our special guest
expert Dr. Vincent DeVita discussing the history of cancer
chemotherapy. Vincent, before the break you were mentioning how
long it now takes in order for protocols to even get up and
running, let alone actually help us get an answer to whether or not
a particular treatment actually works for a particular
cancer.  What is really quite fascinating to me, having been a
product of the National Cancer Institute, and having been one of
your fellows when you were Director at the NCI, is that the NCI was
a very different place that allowed these clinical trials to get up
and running in a very timely fashion and to get us some key
answers.  What, in your view, were the special qualities about
the NCI?  What made it so special that it was able to get
answers that we really needed for our patients?DeVita
 That is a very important question, because in the answer to that
question is the description of what we should be doing now. Cancer
centers were designed in the National Cancer Act "The War on
Cancer" to play a special role in The War on Cancer. What was the
strength of the NCI? We were limited primarily by what was between
our ears. If we had ideas, we could act on the ideas very
quickly.  We did not have to get approval for protocol
modification, which was something that could be handled internally
at the National Cancer Institute.  We could make modifications
very quickly and what now takes 800 days, would take less than a
week at the cancer institute.  We could develop new therapies,
modify them on the run, and come up with very novel ways of doing
things.  I look at the young people now and think why they
even want to do this because you can't spend 800 days waiting while
your protocol is being15:11into mp3 file 
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 approved somewhere else.  I think what needs to be done is
that the Food and Drug Administration and the National Cancer
Institute need to delegate the responsibilities for protocol
development approval for early trials to the cancer centers through
an internal review mechanism so that you can move around very-very
quickly.  There is a wonderful book by Robert Weineberg on
thebiology of cancer.  In the back of the book he has a large
chart that I love to use. It is the most complicated thing in the
entire world; he did it for a reason.  We know a huge amount
about the signaling pathways of cancer cells.  When you look
at it you realize how complicated it is for us to do anything to
interfere with the signaling pathways.  We need to be able to
use the scientific talent at a cancer center to be able to make
modifications to treatment regimens to block various pathways, and
when they do not work, we need to be able to make another
modification very quickly to adjust the treatment.  You cannot
do that by having the protocol submitted back to Washington to the
cancer institute and then back to the Food and Drug
Administration.  Somebody might say, "Dr. DeVita aren't you
concerned about patient's safety?"  I am concerned about
patient's safety.  I think we are not doing something safely
for cancer patients when we make them wait 800 days for our next
best idea.  We are in a very difficult situation and the model
from years ago would be a very good model for us to use again to
readjust the environment of cancer centers like Yale and Harvard.
We have lot of talent at these places and we are not using it as
effectively in this modern age with all the knowledge we have.Chu
 You mentioned the National Cancer Act, which you played a key role
in when you were director of the National Cancer Institute. One of
the key features of the National Cancer Act was to have these NCI
designated cancer centers around the country. One thing that maybe
is confusing to a lot of listeners out there is that there are so
many here in the State of Connecticut, they hear about various
community centers that call themselves cancer centers, but clearly
there is a difference. Could you help our listeners kind of go
through that?DeVita
 I had the privilege of dedicating a number of cancer centers,
including other ones here in New Haven at St. Raphael's
Hospital.  Community cancer centers have a responsibility for
delivering state-of-the-art therapy for particular tumors. 
The cancer centers that were approved and developed by the NCI,
like Yale, have been responsible for developing the
state-of-the-art therapy so being at a cancer center like Yale
brings you closer to the newest developments and since cancer is an
evolving field, you want to stay as close to that if you have a
cancer that is not easily treated at the present time.  The
community cancer centers sprang up, and national mortality rates
have come down for a lot of cancers, and survival rates have
improved because you have been able to take the information from
the cancer centers and spread it out into18:19into mp3 file 
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 the community, but there is a major difference.  The
difference is that one develops the therapy and the other delivers
it. In the process of developing it, you deliver it as well. 
The Yale Cancer Center has to deliver state-of-the-art treatment,
but in the process of doing that, we also have studies that look at
modifying the state-of-the-art therapy to take advantage of the new
biology. For example, when we developed MOPP it took 11 years
fully.  There is a nice paper published on this subject. 
It took 11 years for full dissemination of MOPP into the community;
that was 1967 through 1971 so we did not have all those community
cancer centers out there now.  Now, the modification of a
protocol that is advantageous to the patient can be disseminated
very quickly.Chu
 As you always taught me, translational research is the key to
making new discoveries and bringing new treatment strategies into
the clinic.  Maybe you can tell our listeners out there, what
does translational research mean to you?DeVita
 I am being facetious because translational research is the current
buzz word, so right now when I review grants I never see a grant
that is in transitional research presented to me as transitional
research. But basically, I think what we are trying to say is that
ultimately you have to test new things in patients.  There is
a friend of mine in Boston who always made the rather crude
statement that when he saw a mouse with cancer, he would step on
it, that mouse models do not particularly fit well for
humans.  You have to eventually do your studies in
humans.  Taking basic information and designing studies in
humans is the ultimate goal in translational research, but most
scientists in the lab who are doing something they think may be
relevant will tell you they are doing translational research as
well.  It is a very broad definition that primarily means,
let's try to get something out there to help people.Chu
 One of the exciting aspects these days for those of us who are
involved in cancer drug development, is the ability to work very
closely with the pharmaceutical companies.DeVita
 Yes.Chu
 Which I think may be a bit different than when you were developing
MOPP chemotherapy back in the late 60s and early 70s.DeVita
 There was no pharmaceutical industry in those days.  We were
the pharmaceutical industry.  We had the National Cancer
Institute Drug Development Program.  It was Bristol-Myers
Squibb that was the company that began to put money into and
investing into anticancer drugs, and they did some heroic stuff and
came out with some very good drugs, including the drug Taxol. 
They do a very good job and I think we go a little bit overboard
the other way in trying to avoid conflict of interest in putting
ourselves at arms21:02into mp3 file 
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 length with pharmaceutical companies. I think we need to stay
close to them.  We cannot do at Yale or Harvard or Duke what
the pharmaceutical industry does.  They have the capacity to
develop the drugs, to do the toxicology and to market the drugs, we
don't. So we need to have a partnership with them and what we just
have to be careful about is the extent of that partnership.Chu
 I think that is an important point that you raise, because
unfortunately, with all the press and the media hoopla,
pharmaceutical companies tend to get a very bad reputation, which
sometimes is quite unfair.DeVita
 It is unfair.  I think I have mentioned this to you
before.  I have a pet peeve that is, when you read about these
drugs, new targeted therapies, monoclonal antibodies, the cost of
them can be as much as $100,000 a year, which is a lot of money,
and that is why people pick on the pharmaceutical companies. Then
you hear that they are tested in cancer patients and they only
prolong life by about 3 months, and the public rightly says, you
pay $100,000 a year and you will get a 3 month prolongation of
life.  What is not often said in these articles is that you
are testing it in patients with advanced cancer where it is
beneficial and it is expensive.  When you take the same
therapy and put it in the postoperative period, when there are
fewer cancer cells and the patient can be cured, you may actually
only require about $30,000 worth of drug and the patients are alive
for the rest of their normal life.  So the transition is
always from the expensive and a little bit helpful in advanced
cancer, to less expensive curative approaches in people who have
early stage disease.  I wish when the stories came out in the
newspapers about the big bad companies charging $100,000, is first
of all, it costs about 800 million dollars to develop a drug and
get it to the market. It is happening in breast cancer and it is
happening in colorectal cancer.Chu
 In my own area, in colorectal cancer, where the initial approaches
were to treat metastatic disease, are now actually moving into the
adjuvant setting after surgery and finding remarkable results.DeVita
 Remarkable results, you can say national mortality from colorectal
cancer has plummeted in the last couple of decades.  By the
way, even in advanced diseases you are now starting to see patients
with metastatic disease go into complete remission. Some of those
are lasting a long time and I think we are coming to the point
where we will see the ability to cure patients with metastatic
cancer. However, keep in mind that 90% of the time breast cancer
presents as a local disease.  When you develop these therapies
in advanced disease and then apply them in the local situation, you
are dealing with a great majority of the population, and that is
why mortality rates from breast cancer are coming down in this
country as well.  We need to be careful, but the
pharmaceutical industry in this country is marvelous and the world
owes them23:57into mp3 file 
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 a great debt of gratitude. I think we should continue to work with
them because we cannot do what we have to do without them.Chu      
 I think it is fair to say that the pharmaceutical companies are
quite smart and they partner up with the cancer center programs
that they feel give them the best chance.DeVita
 Yeah.  They do not have the same science that we have and
they can afford to invest into that kind of scientific
program.  They need the scientific input and it is inefficient
for a cancer center to invest in large scale toxicology chemistry
programs to develop drugs, and so we now use them.  The cancer
institute did that for centers for a long time, but it is largely
done by the pharmaceutical industry now.Chu
 Just a minor switch in topics, as I mentioned at the beginning of
the show, you are the senior author of the definitive text in
oncology called Principles in Practice of Oncology, PPO,
now in its eight edition. This is viewed as the Bible by all of us
who practice oncology.  What made you decide to actually write
this book?DeVita
 I just came out last week with the eight edition, so I am very
pleased.  It is a very beautiful book.  We were looking
at the field and we noticed that textbooks came out for surgeries,
medical oncology and radiotherapy, but there was not one textbook
that said, this is cancer, and we put it altogether in one
package.  So I sat down with my colleague, Steve Rosenberg,
who is the Chief of Surgery at the Cancer Institute, and we
convinced Sam Hellman, who by the way was trained here at Yale but
at that time was at Harvard and is one of the preeminent
radiotherapists in the country, to do the book. I remember Sam
Hellman's comment when I asked him, he said "Are you out of your
mind?" Because it was obviously going to take a lot of time and
effort and since the first edition it has been very popular because
I think it filled a need and we like to think, though we're
slightly biased, that the national mortality rates have been nudged
down by making information available to all oncologists in a very
good textbook. Now there are other books that are doing the same
sort of thing and I think it is delightful to see the book doing so
well.  For me, it keeps me sane because what it does is it
forces me to look at the entire field, and we only have a year or
so between editions.  You are constantly looking at what is
changing when you put it together and getting new authors and
making sure that all the new information is in the text.  It
has been a delightful experience.  I do not measure my life in
editions, but I think I would not change working on the text for
much.26:45 into mp3 file 
http://www.yalecancercenter.org/podcast/Answers_July-06-08.mp3Chu
 Vincent, you have got great perspective.  Where do you see
the landscape of cancer therapy heading over the next 5 to 10
years?DeVita
My personal feeling, and I have said this publicly, is that we have
in hand a critical mass of usable knowledge. By that I mean we have
enough information to do what we need to do for most cancers. 
The problem is, as I said, that big diagram in the back of Robert
Weineberg's book is very-very complicated, and sorting it out and
putting it together in effective ways in order to prevent cancer,
diagnose cancer and treat cancer, is very complicated. We need to
be able to develop the machinery to do that.  We paid 55
billion dollars for this information in terms of support for the
cancer program, and right now that is a problem that I am
approaching.  We have a grant that is under review at the
moment looking at the structure of cancer centers and at the
regulatory agencies and their interaction to see if there is a way
we can change things so that we can make use of this knowledge and
move very fast.  If we do, I think the next 10 years are going
to bring startling revelations.  We are going to see tumors we
never thought would fall, fall, and it will happen at a great rate
of speed if we can build flexibility into our programs.Chu
 Vincent, as always, it has been great having you on the show and
hearing your perspectives. We look forward to having you come back
for a follow-up session.DeVita
 Thanks.Chu
 Until next week, this is Dr. Ed Chu from the Yale Cancer Center
wishing you a safe and healthy week.If you have questions, comments, or would like to subscribe
to our Podcast, go to yalecancercenter.org where you will also find
transcripts of past broadcasts in written form.  Next week, we
look at the latest information on kidney cancer with Dr. Harriet
Kluger and Dr. Edward Uchio.  I am Bruce Barber and you are
listening to the WNPR Health Forum from Connecticut Public
Radio.