The Impact of Exercise on Cancer Survivorship

Dr. Melinda Irwin, The Impact of Exercise on Cancer
Survivorship
August 1, 2010Welcome 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 and
the phone number is 1888-234-4YCC.  This evening Francine is
joined by Dr. Melinda Irwin an Associate Professor of Epidemiology
and Public Health at Yale School of Medicine for a conversation
about exercise and cancer.Foss
 Let's start out by talking about this relationship between
exercise and cancer, can you explain it?  Irwin
 For a number of years now, probably about 15 years, we have known
that exercise is related to reducing the risk of getting cancer,
primarily breast and colon cancer, but some other cancers as
well.  More recently, in the past five years or so, research
has been published looking at how exercise can improve prognosis or
survival.  The mechanisms of how exercise decreases risk or
improves prognosis is either indirectly through weight maintenance
or weight control, because the more active you are if you exercise,
you can maintain your body weight, but also directly, so even if
there is no weight loss, just by maintaining your weight, there are
hormonal changes that occur with exercise such as sex hormones or
estrogens where exercising at a moderate to vigorous intensity will
decrease the amount of serum estrogens.  Other hormones are
insulin, and insulin- like growth factors where exercise can
decrease these levels.  And these hormones, the insulin and
insulin-like growth factors and estrogens or sex hormones, are
known to increase cell proliferation or cell growth, so if exercise
can decrease these hormones, then it may decrease cell growth or
delay initiation of a cancer.Foss
 A really important question here at the beginning of the show is,
what is exercise?  It sounds obvious, but I think it has
different meanings for different people.Irwin
 It is a good question because some people may think of exercise as
having to train for a marathon and something that has to be very
vigorous intensity.  That's not the case, in fact, most of my
studies that I conduct are brisk walking, so it is a sustained
activity for at least 10 minutes where you get your heart rate up
to a level that's of a moderate intensity and your breathing is a
little bit irregular.  It is something that we consider that
you do for sustained amounts of time, ideally a 30 minute bout at a
moderate intensity, and generally this is a more recreational
activity such as walking or bicycling, or tennis or swimming. 
Some women and men might consider gardening or household activities
exercise, but to me that is really physical activity, so just by
being more active you are going to maintain your weight, but you
may not see many hormonal changes, so in order to have the more
direct mechanism associated with cancer, it should be something
that's 30 minutes more aerobic type of activity such as the brisk
walking, jogging, or going to a gym and doing activities there such
as stair climb or stationary bicycle.  And other sports as
well like volleyball, golf, if you walk rather than riding in a
cart, skiing, and perhaps some types of dancing.3:33 into mp3 file 
http://yalecancercenter.org/podcast/aug0110-cancer-answers-irwin.mp3Foss 
            
 So it's basically 30 minutes at a time, and how many days a
week?Irwin
 Generally 30 minutes probably five times a week, so about 150
minutes per week is the current recommendation of physical activity
that's necessary for decreasing your risk of certain cancer and
perhaps improving survival or decreasing recurrence.  About
150 minutes per week of something such as brisk walking or
stationary bicycling or another type of activity.  Also it is
recommended that adults do two times a week of resistance training
program, some sort of strengthening program because as we age we
tend to loose bone mass and lean body mass or muscle and that is
what keeps our resting metabolic rate high and so as we age and we
lose bone and muscle, our resting metabolic rate decreases. 
Even if we eat the same amount of foods, we might start to gain
weight because our metabolic rate is lower.  So adding in a
resistance training program is recommended as well.  It is a
little bit more difficult to add in because you have to do it at
the gym.Foss
 Melinda, it sounds like this is not the kind of program that the
average person has right now in their repertoire, so it sounds like
people actually have to dedicate time to do this.Irwin
 Yeah.  Actually, the current recommendation that just came
out last year from the Department of Health and Human Services, is
to decrease sedentary time, so everyone can do that.  If you
are at home, you are sitting and watching TV or you are on the
computer too long, every hour get up and walk around, so decreasing
sedentary time, and then an aerobic activity such as the
walking.  Everyone can walk out the door and go for a walk or
drive to a lovely beach or something like that.  So it is the
resistance training that's more difficult to add into a
routine.Foss
 Great.  I think what you are telling people now is really
important, which is that you can show a direct link between
exercise and these hormones that we know are important not only for
cancer, but for other things as well.Irwin
 Exactly, so some of these hormones are not only related to certain
cancers, but cardiovascular disease and diabetes.  That's what
the great thing about exercise is, it is multifactorial and it
actually improves many chronic diseases and with little or no side
effects associated with it.Foss
 How long have we understood this interaction between exercise and
cancer?Irwin
 About 15 years ago in 1994 was the first publication by Leslie
Bernstein published in the Journal of the National Cancer Institute
looking at how physical activity decrease the risk of developing
breast cancer.  It was an observational study, which is how a
lot of these studies are done.  I do epidemiologic research,
and we look at thousands of patients or healthy people.  In
this case, this study interviewed about a thousand women with
breast cancer and compared them to healthy women without breast
cancer who are matched on certain factors such as age and other6:24 into mp3 file 
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 demographic characteristics and they asked them about their
physical activity levels in their 20s, 30s, 40s, 50s, throughout
their lifetime and they showed that the women who developed breast
cancer, unfortunately, had lower physical activity levels at
different points in their lifetime, and the women who did not
develop breast cancer had higher levels of activity. When we would
statistically adjust for certain factors like disease, stage, and
treatment received, this association still held up.  Since
then, in the last 15 years, there have been 100 plus papers looking
at this observational association of higher physical activity
levels and lower risk of breast cancer and colon cancer.  It
has only been five years since we looked at the association between
physical activity and prognosis or decreasing recurrence risk or
increasing survival.  The first publication came out in 2005,
out of the Nurses' Health Study at Harvard and this publication
followed women who had been recording their physical activity
levels every two years via a questionnaire and these women had
breast cancer.  In about two years after breast cancer, they
looked at their physical activity levels and then followed these
women forward and many developed a recurrence or unfortunately died
from breast cancer, and those who were once again more active, were
less likely to have a recurrence or die from breast cancer.  A
hundred plus studies were done looking at risk and looking at
prognosis, but they are all observational.  There really has
never been any kind of direct trial or definitive trial looking at
increasing exercise on improving survival or decreasing risk. 
And part of the reason is because those studies require a lot of
participants in the study and we have to follow them for many
years.  In place of that, there have been trials looking at
surrogate markers or how randomizing individuals to exercise or to
control would change markers that are strongly related to risk of
cancer or recurrence of cancer such as these hormones and that is
the basis of my research, how exercise can improve these surrogate
markers or these biological markers related to cancer.Foss
 When we look at these big studies like the Nurses' Study and the
Framingham Heart Study those are basically long term longitudinal
studies looking at a number of different factors and trying to
integrate those to an outcome. So with respect to exercise, say in
that kind of a study, how good is that data given that a lot of it
is retrospective over time.Irwin
 The nice thing is that if you find an association, and usually we
find about a 30% to 40% reduced risk of say developing cancer or
decreased risk of recurrence among those who are active about doing
this two and a half hours per week, versus those not doing
activity, if you had a methodologically stronger study, you would
probably find an even stronger association.  So observing
these associations, given the fact that it is women and men just
completing questionnaires about their lifestyle, there can be some
misclassification or bias on how they report their activity. 
We know there is a social desirability bias and people may over
report how much exercise they are actually doing.  In turn, if
we are recommending 150 minutes per week or two and a half hours
per week of exercise and we know people tend to over report, it may
be that we9:51 into mp3 file 
http://yalecancercenter.org/podcast/aug0110-cancer-answers-irwin.mp3actually only need to do two hours or only an hour and a half
per week of exercise to improve our risk or decrease our risk of
recurrence.Foss
 That leads me to a good question which is, how did you come up
with that number?Irwin
 The number of two and a half hours a week of physical activity was
first based on cardiovascular disease and then last year there was
a panel convened to look specifically at cancer.  So it's
really looking at the data in detail by cancer type and by type of
exercise, and the strength of the study. If it was a study that did
not have a large enough sample size, it was not included in the
analysis and then looking at the questionnaire used to
measure physical activity.  So the strength of the studies
that were included in this kind of consensus statement show that it
was about 150 minutes per week and it showed that those who did
more than that amount of physical activity did not have a stronger
benefit than those who did not.  In fact, the risks improve
with any amount of physical activity and then it kind of leveled
off around that 150 minutes per week.  Something really is
better than nothing if you only have time for say 30 minutes a week
that is better than doing nothing.Foss
 Great, that's an important message.  Can you talk about other
cancers?  We have talked a lot about breast cancer because
that's primarily what the major studies were in, but what about
prostate and lung, and some of those other common cancers out
there?Irwin
 The reason the majority of research has been done in breast and
colon cancer is because those are common cancers, and so it's
easier to recruit men and women into those studies and have them
complete information.  But there is emerging data, every month
there are more publications looking at the role of physical
activity with prostate cancer, with ovarian cancer, endometrial
cancer, non-Hodgkin's lymphoma, and leukemia so there are a growing
number of studies.  They are not all consistent, they may show
only 20% improvement and another may show 40% improvement or
another study may show it trending in the right direction but it is
a non-statistically significant finding. Basically we need more
studies done in this field to really be able to come to more
conclusive findings.  But it is pointing in the right
direction and the mechanisms are similar as with the other
cancers.  Prostate cancer is similar to breast cancer in that
testosterone for men is similar to estrogen with women and how it
could increase risk of prostate cancer.Foss
 Do we know yet how important the age is that you start exercising,
say if you started it in your 50s is that just as good as if you
started it in your 30s?Irwin
 I will tell you about a paper that I have under review from the
Women's Health Initiative, which is a large study of 100,000 plus
women around the country and the nice thing about this study is it
recruited post menopausal women, healthy women, and they completed
questionnaires every two12:55 into mp3 file 
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 years, it was an observational study, and there were some clinical
trials looking at dietary components.  We had questionnaires
from all these women and then about 5000 women developed breast
cancer and they continued to complete the questionnaire.  We
were able to look at the physical activity levels before diagnosis
and after diagnosis.  Looking at before diagnosis, we observed
a decrease risk for breast cancer, but then also when we looked at
recurrence and death, we showed their physical activity before and
after diagnosis improved their prognosis.  So those who may
have been inactive before diagnosis, but initiated an exercise
program after diagnosis, had a reduced risk for recurrence. 
Even if you are postmenopausal when you are diagnosed and you
haven't participated in exercise, if you initiate after your
diagnosis, you can have an improved prognosis.Foss
 That is a really important message to get across to women.  I
would like to talk a little bit more about that when we come
back.  Stay tuned to learn more about exercise and cancer with
our guest, Melinda Irwin.Foss
 Welcome back to Yale Cancer Center Answers.  This is Dr.
Francine Foss and my guest Melinda Irwin joins me today to discuss
the issue of exercise and cancer.  Melinda, in the first part
of the show we talked a lot about observational studies linking
exercise with decreased risk of cancer and I am wondering, could
you talk a little bit about some of the work that you are doing
because I understand that you are actually looking at this issue in
more detail.Irwin
 While the observational research is really encouraging in showing
the benefit of exercise, unfortunately it may not be enough to
convince some clinicians out there or oncologists of the benefit,
and it probably is not enough to convince the insurance companies
to reimburse exercise15:53 into mp3 file 
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 programs for cancer survivors or those who are at risk of
developing cancer.  My research is really focused on doing
randomized control trials to look at how increasing exercise may
actually improve prognosis, decrease recurrence, and improve
survival among women with cancer.  Specifically, my research
is looking at breast cancer and ovarian cancer.  I'll quickly
talk about that trial in breast cancer, which was initiated last
year and it was a result from some of my studies done previously
looking at if exercise is feasible among women with breast cancer
during treatment and post treatment, and it is associated with
improvements in some of these biological markers.  I was
interested in looking at how exercise can improve some of the side
effects of treatment.  Women with estrogen receptor positive
breast cancer, their tumors that are estrogen receptor positive,
they are given hormone therapy, aromatase inhibitors, to block
their estrogen activity and this is the standard of care for most
women with breast cancer.  Unfortunately, some of these women
are discontinuing their treatment because of the side effects of
the hormone therapy such as joint pain, bone loss, hot flashes, and
we know that exercise improves rheumatoid arthritis or
osteoarthritis and so given the joint pain or the arthralgias, one
of the most common side effects and it is associated with
discontinuation of treatment, we are looking to see if exercise can
improve arthralgias, and if it can improve bone mass, as well as
looking at the mechanisms such as inflammation.  So CRP, or
C-reactive protein, is a marker of chronic inflammation, and if
exercise can improve CRP, improve joint pain, and arthralgias, it
may in turn improve adherence to taking the aromatase inhibitor and
then indirectly improve survival.  That is one trial we have
ongoing and we are recruiting for two years for that and if we show
that it improves adherence to the treatment as well as decreasing
side effects, maybe insurance companies will think about offering
reimbursement for certain exercise programs that are either offered
through the hospital or the community. The second study that I have is looking at women with ovarian
cancer and this is a really exciting study that was initiated last
year and it is exciting because most of the research in women with
ovarian cancer is looking at treatment, so how to improve different
chemotherapy regimens or if chemotherapy should be done before
surgery or post surgery, but very little research is focused on how
lifestyle may influence their quality of life and prognosis. 
We know that women with ovarian cancer unfortunately have a worse
quality of life than other women diagnosed with other cancers,
partly related to the high recurrence rate and unfortunately low
survival rate.  We are enrolling women about six months after
their diagnosis of ovarian cancer to a home based physical activity
program where our certified trainer and counselor calls them weekly
at a convenient time and motivates them to increase their walking
to the recommend amount of 30 minutes five days a week, and then we
look at how this improves fatigue, peripheral neuropathy, cognitive
function, lower limb lymphedema, which has been unrecognized in
ovarian cancer patients but we are also taking a sample of blood at
baseline and six months after the intervention to look at if it can
improve certain hormone markers such as CA 125 or lactin, or IGF-2
or insulin. Some of these markers we know are related to ovarian
cancer risk and prognosis.  If we show a benefit of exercise
then it could also be recommended by a clinician and covered by
insurance companies. 19:37 into mp3 file 
http://yalecancercenter.org/podcast/aug0110-cancer-answers-irwin.mp3That's the research that is going on and for two years we will
be recruiting for that, then there are some larger initiatives that
I am involved with that are not just here at Yale but that are
multi-site around the country. For example, the National Cancer
Institute funded a large initiative called TREC, Transdisciplinary
Research on Energetics and Cancer where we look at interactions
between physical activity, diet, obesity and certain genetic or
molecular markers and environmental factors and how it can improve
your risk and prognosis.Foss
 This sounds really exciting that we are now looking at symptomatic
issues as well in cancer patients in addition to just preventing
the cancer. What you are talking about with these specific cancers
can that be applied to other patients with cancer as well, say
prostate patients, colon cancer patients, would they expect perhaps
to do better with their treatment if they exercise?Irwin
 Definitely.  Since we know cancer related fatigue is quite
common with most cancers, whether it be because of chemotherapy or
because of radiation therapy, exercise is not only going to affect
say breast cancer patients, it will have a similar affect with
colon, prostate, endometrial, all these other cancers.  There
have been studies looking at exercise done during treatment, during
chemotherapy, during radiation therapy, and then also post
treatment and most of the findings have shown there is no reason to
delay initiation of an exercise program and that, in fact, if you
begin it during treatment than it could decrease your levels of
fatigue.  There is also some research showing that it
increases your chemotherapy completion rate, so that by being
active or involved in a moderate intensity exercise program during
treatment, you may be able to better handle the chemotherapy. 
There have been some studies done looking at doing just a month
long exercise program before surgery, and if that can improve your
surgery with less time in the hospital perhaps and less side
effects from the cancer related surgery.  Whether it is
exercise before surgery, after surgery, during treatment or post
treatment, to me, I think, the patient has to look at their
lifestyle and their work history and their family demands and stuff
and when they can fit it in, but at any one of those time points,
or all of those time points, there is definitely benefit of
physical activity in improving side effects of surgery and
treatment and then eventually improving survival.Foss
 As you mentioned at the beginning of the show, it just requires
going out the front door of your house and walking, it does not
require a health club or a trainer or anything like that.Irwin
 It of course requires you to look at your schedule and figure out,
how do I prioritize, how do I fit it in? It's difficult with, say
radiation, if you are going five days a week for therapy, and
that's why if these hospitals or community centers where treatment
is delivered had some sort of exercise program, trainers, or
physical therapists to initiate a program, that would really
help.  The one good thing is that we have the Connecticut
Challenge Survivorship Program here at Yale Cancer Center where
patients can be referred to this program to receive information on
how to increase22:51 into mp3 file 
http://yalecancercenter.org/podcast/aug0110-cancer-answers-irwin.mp3exercise and there are other programs too on nutrition and
smoking cessation and other benefits, so that's the benefit here
having that program to get instruction on how to begin a
program.Foss
 If a woman wanted to participate in one of your trials, ovarian or
breast cancer trial, how would they go about doing that?Irwin
 They can contact our study phone number which is (203) 764-8426,
or they can email me at Melinda.Irwin@yale.edu ,
or they can call Yale or go to the Yale website and either type in
exercise and cancer and it might pull up a link to my web page.Foss
 Great.  Is it your hope as a result of your research that a
lot of this is going to be covered and provided by insurance
companies as part of comprehensive care for patients?Irwin
 Definitely, that has been an ultimate goal of mine. Similar to
cardiac rehab programs, it used to be 20, 30, 40 years ago that if
someone had a heart attack they were told to go home and rest and
they then realized that was the worst thing to do after a heart
attack or surgery for heart disease. You had to get up and initiate
some sort of program because what's putting you at risk for heart
attack is carrying groceries or mowing the lawn or raking so you
have to train your body to be able to withstand these physical
activities.  Similar to a cancer diagnosis, there should be
cancer rehab programs even if it is just a 12 week long program,
similar to cardiac rehab, that's a first step.  We have made
some advances, for example, just last year I was involved in a
panel from the American Cancer Society, American College of Sports
Medicine, where we developed a certification for personal trainers
or physical therapists to take and get certified to train patients
with cancer and how to adopt or modify an exercise program if they
have lymphedema for example, and so by working or training with one
of those certified trainers, insurance companies may recognize that
as a first step and cover those sessions.Foss
 That's a huge advance for cancer patients.  Can you tell us a
little bit about the Cancer Prevention and Control Research Program
at Yale?Irwin
 I co-lead the Cancer Prevention and Control Program here with Yong
Zhu who is also the other co-leader and we are one of seven
programs at the Cancer Center and we have two main themes in our
program.  The first is to look at what causes cancer, and a
lot of that is sort of the epidemiologic research.  We look at
how genetic factors, environmental factors, or lifestyle factors
may cause cancer, and so those are the observational studies, the
case control studies, or the cohort studies, and we look at
interactions between, for example, gene and environmental factors
and how it may cause cancer.  The second theme is these
behavioral trials that I focus my research on.  So, how a25:42 into mp3 file 
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 weight loss program, an exercise program, or smoking cessation and
alcohol, how these programs for risk of cancers or in prognosis,
can improve their cancer outcomes.Foss
 You mentioned the issue of a randomized controlled trials and I
wonder if just for the sake of our audience, you could talk about
the difference between the observational trials and these
prospective randomized control trials and what the control group is
in these trials?Irwin
 That's a very good question.  In my studies that are with
breast and ovarian cancer patients, our control is usually standard
of care, so what the clinician is recommending that their patient
do either during treatment or post treatment, but we actually
enhance it a little bit.  In my trials, we have what's called
a health education, so both groups get health education and then
the exercise group gets exercise on top of the health
education.  What we offer them for the ovarian study, which is
6 months long, is a weekly health education topic that we find
important to women with ovarian cancer, peripheral naturopathy,
lower limb lymphedema, or fatigue related to chemotherapy or how to
find information on the web, so both groups get that. 
Actually the control group is getting a little bit more than what
the standard of care actually is.  But unfortunately, some of
the participants they want all want the exercise program, so at the
end of the trial we do offer them three, one-on-one sessions with
our trainer and we develop a personalized exercise program for
them.  But it's really important to do randomized control
trials compared to observational studies to show that you are
controlling for all these other extraneous factors that could
really be explaining the association. We want to zero in on the
fact that it's physical activity or exercise that's improving risk
or improving prognosis, and as I mentioned, physical activity can
improve say chemotherapy completion rates.  Is it those who
are active that are actually receiving more chemotherapy and that's
why their survival or prognosis has improved, or is it the
exercise?  So you need to do these randomized trials to
isolate what the factors are improving the outcome.Foss
 Normally when we do say drug trials in cancer, we enroll say 30 to
100 patients, and for these epidemiologic studies you need far more
patients.Irwin
 Yes, we need more patients because of the completing of
questionnaires or collecting blood samples.  There can be some
variability in the serum hormone levels from day to day, and in the
questionnaire, as I mentioned, social desirability bias.  So
the more participants you have on a trial, you can actually look at
the association a little bit stronger.  In drug trials, or in
studies with animals, you can really get at the exact measure, so
you can have smaller sample sizes.  In my studies, in the
randomized trials, it's about 200 to 300 participants and in the
large observational studies it might be 1000 participants. 
It's anywhere from about 200 to 1000 participants, which is a lot
more then say 50 or less that may be needed for some other types of
trials in animal studies or something.28:53 into mp3 file 
http://yalecancercenter.org/podcast/aug0110-cancer-answers-irwin.mp3Foss
 Melinda, in the last minute or two can you tell us about any other
exciting research that is going on?Irwin
 As I mentioned there are a lot of trials here at Yale going on and
we have a lot under review, some looking at women with high risk,
who might have BRCA1/2 mutation and we are going to actually look
at cell proliferation in the breast tissue and collect some of the
breast tissue and look at the cells and the rate of proliferation.
We are trying to get as exact of a mechanism as we can and then
throughout the country there are lots of studies being done in
other cancers as well to really strengthen the association.Foss
 This has been a really exciting discussion Melinda, and we will
have to have you back to hear the results of those ongoing
studies.Irwin
 Great, thank you.Foss
 The message for everybody is continue to exercise.  Until
next week, this is Dr. Francine Foss wishing you a safe and healthy
week.If you have questions or would like to share your comments,
visit yalecancecenter.org where you can also subscribe to our pod
cast and find written transcription of past programs.  I am
Bruce Barber and you are listening to the WNPR Health Forum on the
Connecticut Public Broadcasting Network.