Symptom Science and Cancer Survivors: Lessons Learned, Opportunities, and Challenges – A Personal Perspective

July 01, 2024

Information

Yale Cancer Center Grand Rounds/Iris Fischer Memorial Lecture | June 28, 2024

Presented by: Dr. Patricia Ganz

ID11848

To CiteDCA Citation Guide

00:04Hey, Joel. Why don't we
00:05get going?
00:08As I explained to our
00:09speaker, we're still sort of
00:11struggling getting people back in
00:12person,
00:13but we know that there
00:14are many people online.
00:16So it's a real pleasure,
00:19to have Patty Gans here
00:21today,
00:23to give the Iris Fischer
00:25Memorial Lecture.
00:27I have known Patty for,
00:30just a few years or
00:31maybe just a few decades.
00:34And when I was a
00:35young faculty member interested in
00:37issues related to
00:39quality of life and survivorship,
00:43Patty was about the only
00:45person doing this.
00:47And I think it's fair
00:49to say, and I, said
00:51this at dinner last night,
00:53that Patty is really the
00:55senior statesperson
00:57when it comes to work,
00:59particularly in breast cancer, but
01:00across malignancies
01:02related to
01:03survivorship,
01:04quality of life, late effects
01:05of therapy.
01:07And, you know, at a
01:08time when
01:09I think most,
01:11medical oncologists and other cancer
01:13physicians and researchers were focused
01:15on just
01:16giving more and
01:18sort of pounding away at
01:19people.
01:20Patty was asking questions about
01:22what does that mean for
01:23people after the fact, and
01:25that,
01:26is more relevant today
01:28than, ever before.
01:30I will not detail all
01:32of the awards
01:33that you have won.
01:36Patty is a member of
01:37the National Academy of Medicine
01:40and is just,
01:42both renowned
01:44and beloved,
01:45in the breast cancer community
01:47and the psychosocial oncology community
01:50and survivorship community. So, Patty,
01:52thank you so much for
01:53being here, and,
01:55it's all yours.
02:00Thanks. And I I'm glad
02:02that Eric moved the microphone
02:04because I'm also
02:05vertically challenged
02:07a little bit. So it's
02:08great to be here today,
02:10and, I really appreciate the
02:11welcome and also the opportunity,
02:14to share, which I think
02:15will be a multiple decade
02:17experience. And,
02:18just to to let you
02:20know, you know, how my
02:21career evolved, but really the
02:22focus on symptom science.
02:24So just a couple disclosures
02:27here.
02:30Okay.
02:30So what am I gonna
02:31be talking about? Well, I'm
02:32gonna be sharing my journey,
02:34and you already heard from
02:35Eric about, you know, how
02:36I kind of began to
02:38work in this area, And
02:39I've really been very fortunate.
02:42I was really in the
02:43early days working on quality
02:44of life and symptom measurement
02:45in clinical trials. And I
02:47work Liosha and I were
02:48just talking about a trial,
02:50that I'm analyzing the quality
02:52of life for. So I
02:53really
02:54began
02:55in that way when people
02:56were trying to say, could
02:57we scientifically measure,
02:59patients' experiences with,
03:02their treatment and disease?
03:04Then I wanna talk about
03:05my interaction between my own
03:07research and what I learned
03:08from assessing quality of life
03:10outcomes in clinical trials and
03:11how I then began to
03:13bring that back to my
03:14own research. And then lastly,
03:16to talk about advancing the
03:17whole field of symptom science
03:19in cancer survivors
03:20and really the need for
03:22collaborative team science. And I
03:23think that's really what cancer
03:24center is about cancer centers
03:26are about is to try
03:27and do that kind of
03:29translational work.
03:31So
03:32this was about nineteen ninety,
03:33and this was a conceptual
03:35model that was put forth
03:36in terms of talking about
03:37quality of life. And there
03:38had already been a lot
03:39of social science research
03:41trying to measure the health
03:43and well-being of the general
03:44population
03:45that came out of the
03:46Johnson administration,
03:47the war on poverty, a
03:48lot of things that were
03:49done. How can we measure
03:51well-being? And that was then
03:52beginning to be adapted
03:54to applying it to health
03:56health and health well-being and
03:58health related quality of life.
03:59And cancer, of course, because
04:00of the toxicity of our
04:02treatments,
04:03was the poster child for
04:04trying to be able to
04:05look at this. So you
04:06can see we have quality
04:07of life at the center,
04:08but look at all the
04:09other things that are being
04:10measured,
04:11symptoms and side effects, social
04:12functioning, physical functioning, and psychological
04:15functioning. So this was one
04:16way of kind of conceptualizing
04:18how to measure this. This
04:19was another way to kind
04:20of break these things down
04:22a little bit. But what
04:23I'm pointing out here is
04:24that symptom status was always
04:26part of what people were
04:27thinking about as quality of
04:29life. You know, when we
04:30think about the pro CTCAE
04:31now, which is kind of
04:33looking at toxicity from treatment
04:34but is also looking at
04:35symptoms,
04:36people think that's a separate
04:38thing, but it is really
04:39a component
04:40of quality of life.
04:42And in this next slide,
04:43really, I wanna point out
04:45that
04:46when you ask somebody overall,
04:47how is your quality of
04:49life or how are you
04:50feeling today, thinking about walking
04:52down the corridor in the
04:53hospital or in in near
04:54your clinic and saying, how
04:56are you today? You're kind
04:57of asking that global question,
04:58and the person that you're
05:00talking to might say, oh,
05:01yeah. Everything's okay. But if
05:03you really started to ask
05:04them, their back is bothering
05:06them, they didn't sleep well
05:07last night, and they may
05:08have a variety of symptoms
05:10that really they're kind of
05:12putting together to give you
05:14that global assessment. And here,
05:16if we see patient a
05:17and patient b, we can
05:18see patient a has a
05:20decreased functional status. But if
05:22we look at patient b,
05:24it's pretty good. If we
05:26look at disease symptoms, there
05:28are a fair number in
05:29patient a that's low,
05:31but better
05:32in, patient,
05:33b over there. But, again,
05:35just the the point here
05:36is both of them have
05:37the same global assessment of
05:39quality of life, and you
05:40really do have to dig
05:41down and look at those
05:42domains to understand
05:44what people are experiencing and
05:46how they're evaluating
05:48that global rating.
05:50This is another model, again,
05:52from the nineteen nineties from,
05:54Clear Wilson and Cleary, who
05:55really were not just doing
05:56this for cancer, but really
05:58overall looking at quality of
05:59life. And you can see
06:01on the left are the
06:02biological and physiological
06:03variables, but then symptoms are
06:05how things are manifested in
06:07the patient. And, again, you
06:09can see cancer therapy coming
06:10in there, if you will,
06:12intruding
06:13and causing new symptoms for
06:14someone. And over at the
06:16right, I've circle
06:18circled
06:19nonmedical factors, which, again, we
06:21now talk about social determinants
06:22of health. And again, we're
06:24always part of these things,
06:25but we're now beginning to
06:26pay more attention.
06:28But if we look again,
06:30the patient comes to the
06:32illness with preexisting
06:34conditions,
06:35and we very seldom actually
06:37pay attention to this. This
06:38is what I call host
06:39factors, the life experience. Did
06:41they have depression before? Did
06:43they have other chronic illnesses?
06:45And so this is the
06:46soil, if you will, in
06:47which our cancer treatment starts
06:49to cause problems or symptoms
06:51in patients. And, again, there
06:52are the characteristics of the
06:54individual part of that life
06:55history,
06:56their personality and other issues,
06:58and then their social
07:00support and environmental context. All
07:02of these things really need
07:04to be considered, but we
07:05seldom do that except if
07:06we have the luxury of
07:07doing a very comprehensive
07:09study where we're asking a
07:11lot of questions of people.
07:13So now I wanna start
07:14to show you a little
07:16bit of data from some
07:16of the clinical trials work
07:18that I've done over time,
07:19where I wanna point out
07:20that symptoms really are influencing
07:23all these domains. And this
07:24is baseline data from the
07:26breast cancer prevention trial, which
07:27was conducted in the nineteen
07:29nineties. I had the good
07:30fortune of being able to
07:31do the, the quality of
07:33life study for the b,
07:34b BCPT,
07:36the p one trial. But
07:38look, that symptoms here are
07:39all highly correlated
07:41with all of those domains
07:42on the left, whether it's
07:44pain or physical functioning,
07:46mental health. So really understanding
07:48the symptom profile of the
07:49patient may be very important
07:51to both improving their quality
07:53of life as well as
07:54understanding what they're experiencing. And
07:56those were all women before
07:58they ever started tamoxifen or
08:00a placebo. So these are
08:01midlife women. And here is
08:02some more data from that
08:04particular study where you can
08:05see by age, the dark
08:07blue are the women thirty
08:09five to forty nine. The
08:10yellow are the women fifty
08:12to fifty nine, and the
08:13aqua are the women over
08:15sixty. And so I'm pointing
08:16out with the arrows here
08:17that women fifty to fifty
08:19nine, not on any Tamoxifen
08:21yet, but just in that
08:23perimenopausal
08:24menopausal period of time, are
08:26having hot flashes, night sweats,
08:28vaginal dryness, and joint pains.
08:30And joint pains do grow
08:31up as women age, and
08:32we all know that. And
08:33if we think about aromatase
08:35inhibitor therapy that we're giving
08:37to women with breast cancer,
08:38you can see why joint
08:39pains become such a big
08:40problem. So this is just
08:41the importance of looking at
08:43these symptoms. And again, the
08:44host factor here being age
08:46influencing this and the context.
08:49This is also, from the
08:51p two trial, the STAR
08:52trial, where we compare tamoxifen
08:55to raloxifene in healthy women.
08:57And the first two panels,
08:58the SF thirty six mental
09:00and physical component show you
09:02that there's complete overlap. And
09:04the women are actually very
09:05highly functional in terms
09:08of the scores. Fifty is
09:09the average for the population.
09:09They're above
09:10volunteers from a for our
09:12clinical trial have higher
09:14psychosocial
09:15functioning. And their physical functioning
09:17declines a little bit, and
09:18their depression doesn't really change
09:20very much with the treatment.
09:22But again, I wanted to
09:23show you when we looked
09:24at the symptoms in the
09:25trial, we could, in fact,
09:26see that there were differences
09:28between raloxifen and tamoxifen.
09:30And on the panel here,
09:33here, if we look at
09:34vasomotor
09:34symptoms, we can see that
09:36women who were over age
09:37sixty,
09:39had fewer vasomotor symptoms with
09:41either of the drugs than
09:42the women who were younger.
09:44And, again, if we look
09:45at leg cramps, we can
09:46see, there's a difference between
09:48the two drugs. So, again,
09:50very valuable to be looking
09:51at symptom profiles even when
09:53the global
09:54quality of life domains don't
09:56seem to be affected.
09:58And again, another trial, this
10:00was the b thirty five
10:01trial. Again, I've had a
10:02long term collaboration with NSABP
10:04NRG Oncology,
10:06but this was a trial
10:07looking at, tamoxifen
10:09or aromatase inhibitor anastrozole
10:11in women who had DCIS,
10:13so a very low risk
10:15situation.
10:16But we can see again
10:17here for these curves, the
10:18physical component scores comparing the
10:20two drugs. There's no difference.
10:22But if we look at
10:23hot flashes vasomotor symptoms, tamoxifen
10:26has a worse profile, more
10:27symptoms
10:28in these women. And musculoskeletal
10:31pain, again, no surprise, is
10:33higher,
10:34with the anastrozole. So we
10:35can see these patterns. And
10:37why is this important? Well,
10:38then we can talk to
10:39our patients about this. This
10:40is information that we can
10:42share in the clinic.
10:44So I wanna talk about
10:45some early parallel research going
10:47on in my own laboratory.
10:49I was very fortunate,
10:51because early in my career,
10:53UCLA had a cancer cancer
10:55control,
10:56p o one, and I
10:57was invited actually,
10:59this was in nineteen eighty
11:00three, to put in a
11:01project. And this was my
11:03first foray in beginning to
11:04look at the impact of,
11:06patients' experience from treatment, and
11:08I hope to recruit
11:09newly diagnosed breast and colorectal
11:11cancer patients.
11:12And just to say, at
11:14that time, in the early
11:15eighties, already breast cancer treatment
11:17was sort of organized, so
11:19you could go to a
11:19breast clinic or a surgeon's
11:21practice and be able to
11:22get those patients. But the
11:23colorectal cancer patients in Los
11:25Angeles were treated all over.
11:28People, if they had had
11:28their gallbladder surgery before, they
11:30went to the same surgeon
11:31for their colon cancer that
11:33they had their gallbladder surgery
11:34with and so forth. So
11:35it was very hard to
11:36recruit those patients. And, be
11:38that as it may, it
11:40wound up mostly we were
11:41able to get breast cancer
11:42patients, and then I became
11:43an expert, if you will,
11:45in following these,
11:46activities and outcomes. And we,
11:48in fact, followed patients for
11:50the first year after,
11:51their treatment, with, breast cancer
11:54surgery and did a randomized
11:55trial, which was a failed
11:57trial. I could tell you
11:58about that. But we had
11:59a lot of good descriptive
12:00data about the experience
12:02of women with that. And
12:04because we had followed these
12:05women for a year, I
12:07realized that some things were
12:08getting better. Physical functioning was
12:10getting better, but the psychosocial
12:12function didn't recover and sexual
12:14function was terrible. So I
12:16was able to get some
12:18funding from the American Cancer
12:19Society to follow this cohort
12:21further, and I was able
12:22to follow them for two
12:23or three years later. And
12:24that, achieved some new information
12:27particularly about sexual
12:28health. And then when there
12:29was an RFA,
12:31from the NCI in the
12:32early nineties,
12:33I was able to get
12:34an r o one to
12:35look at sexuality and intimacy
12:37in breast cancer survivors. And
12:38I did this study with
12:39Julia Rowland in Washington where
12:41she was at Georgetown before
12:42she became,
12:43director of the Office of
12:44Cancer Survivorship.
12:46And we focus particularly on,
12:48women who were about a
12:50year out after treatment,
12:52did a couple of very
12:53large,
12:54studies in terms of cross
12:55sectional data and recruited them
12:57for an interventional study and
12:58tried to also focus on
13:00African American women.
13:02Again, because I was beginning
13:04to see all these symptoms
13:05in our patients who we
13:06were doing in our following
13:07in our research, I noticed
13:09again, managing menopausal symptoms was
13:11really problematic.
13:12And I was able to
13:13get funding from the department
13:14of defense, which was newly
13:16organized at that time. This
13:18was again a failed grant
13:19application to the NIH where
13:21mostly the male reviewers said,
13:22oh, those are not problems
13:24for women with cancer.
13:26But finally, the DOD actually
13:28appreciated
13:29the fact these were issues.
13:31And then,
13:32again, I was able to
13:33get a core grant supplement
13:34to look at, the issues
13:36in younger women with breast
13:37cancer. And this is when
13:38I first began to look
13:39at these issues,
13:41not only in terms of
13:42bone health, cardiovascular
13:44health, but beginning some of
13:45the work on cognitive function,
13:48in women after breast cancer
13:49treatment, focusing on these issues,
13:51in younger women in particular.
13:54So what did I learn
13:56from these studies? Well, again,
13:57I've already mentioned the host
13:58factors.
13:59What the patient brings
14:01to their cancer diagnosis is
14:03very important. And if you
14:04could just think, if you're
14:05a clinician and you're seeing
14:06a patient, and if you
14:08could just ask the patient,
14:09have you ever had an
14:10episode of depression in your
14:12past life? Okay. That's one
14:14question that would be very
14:15valuable because we know that
14:17people who have had a
14:18past episode of depression are
14:20more likely to have another
14:21episode. And the if you
14:23will, the trauma and the
14:24difficulties of having a cancer
14:26characteristics
14:28of
14:30the
14:33tumor and whether maybe somebody
14:34can tolerate that treatment. But,
14:34again, many things we don't
14:34ask about. We focus on
14:34the tumor and we focus
14:34on characteristics of the tumor
14:36and whether maybe somebody can
14:37tolerate that treatment. But we
14:39don't really know what someone
14:40has experienced before, which may
14:42influence all of the symptoms
14:44after their treatment.
14:46Again, the importance of collaborative
14:48team science. I have had
14:50the good fortune to work
14:52with many social scientists, particularly
14:54psychologists, some psychiatrists
14:56since the beginning. That first
14:57grant that I had, was
14:59with a psychologist and a
15:00psychiatrist. And so very valuable,
15:02to be able to do
15:03that because I had no
15:04methodological
15:05training. When I mentor people
15:07today, I say, you need
15:08to get that master's degree.
15:10You need to get that
15:10PhD. Whatever it is, you
15:12need to learn that science
15:13because we do not learn
15:15that in medicine. And, again,
15:16I've had a lot of
15:17basic and translational collaborators as
15:19well.
15:20And then the next message
15:21here is to never do
15:22a survey or an intervention,
15:25without either collecting clinical data
15:27or biological
15:29And again, if we need
15:30to move the translational needle
15:32on this kind of research,
15:33we need to look comprehensively.
15:36So it's not just enough,
15:38to do that survey.
15:40And then the value is
15:41I've already indicated about building
15:44on past observations and findings,
15:46especially when they complement the
15:48clinical experience. And again, because
15:50I'm a clinician,
15:51I have been able to
15:52move back and forth from
15:53the clinic when I begin
15:54to hear about new symptoms
15:56or or problems a patient
15:57has that then becomes a
15:58point of investigation.
16:00But also,
16:01if I'm investigating something or
16:03doing research or trying to
16:04manage those symptoms in a
16:05new trial, I can recruit
16:07those patients. I can also
16:09do what I learn
16:11in the clinic from the
16:12studies that we've done.
16:14So
16:15again, the importance of my
16:17parallel medical oncology practice just
16:19as I was alluding to.
16:20Again, I was, again, in
16:22the very beginning, taking care
16:23of patients at the VA
16:24with very advanced cancer, running
16:27a palliative care and rehabilitation
16:29ward. But, again, because of
16:31the focus of my research
16:32and my move back to
16:34UCLA full time,
16:35my practice is really focused
16:37on breast cancer patients.
16:39And then, in the nineteen
16:41nineties, with the emergence of
16:42high dose chemotherapy treatment, which
16:44we all know was a
16:45failed experiment,
16:47unfortunately,
16:47but it did lead to
16:48a lot of toxicity. And
16:50we were able to observe
16:51that, unfortunately,
16:53and fatigue, cognitive difficulties, and
16:55menopausal symptoms really kind of
16:57became preeminent in managing the
16:59aftereffects from these treatments
17:02as well as the more
17:03widespread use of of chemotherapy.
17:06And, again, having lived through
17:08all of these decades of
17:09changes in treatment of breast
17:10cancer, I can say, you
17:12know, there's great enthusiasm
17:13around the turn of the
17:14last century this last century
17:16to give everybody chemotherapy. And
17:17if you had a tumor
17:18that was larger than a
17:19centimeter in size, you got
17:21chemotherapy. And that meant a
17:23lot of early stage breast
17:24cancer patients were being exposed.
17:26And so there was a
17:27big pool of people now
17:28who were getting chemotherapy.
17:30And before the anthracyclines
17:32were popularized, CMF was very
17:34popular.
17:35That caused probably more cognitive
17:37difficulties than we see with
17:38some of the other regimens.
17:40And so I was beginning
17:41to see more people in
17:43my practice
17:44who were having these kinds
17:45of persistent symptoms, and that's
17:47really when I embarked
17:48on what I would say
17:49the last two decades of
17:50work, which has really been
17:51focusing
17:52primarily on fatigue and cognitive
17:54function.
17:55And I think the good
17:56message here is that with
17:57the advent of genomic tests
17:59for breast cancer, in particular
18:01but other tumors, we can
18:02be much more specific in
18:04who gets the exposure to
18:05chemotherapy and who does not
18:07need it anymore, which again
18:08is really very important for
18:10us in minimizing the morbidity
18:12of, cancer treatments.
18:14So just to point out
18:16now in terms of talking
18:17about survivors,
18:18it's really wonderful,
18:20for us to see so
18:21many people surviving cancer.
18:23Again,
18:24eighteen million, probably more today,
18:26but this is some some
18:27data that we have. And,
18:29again, just to point out,
18:31this is about five percent
18:32of the US population. Okay?
18:34So there's nothing to, you
18:35you know, be,
18:37surprised about, if you will.
18:38It's a number of people
18:39that we need to be
18:40very concerned about.
18:41And thinking about, who's surviving
18:44and how long, you can
18:45see here data from the
18:46National Cancer Institute
18:48that there are a large
18:49number of people who are
18:50living fifteen, twenty, thirty years
18:52out.
18:53Women have, slightly greater survival
18:55than men because of the
18:56kinds of tumors that they
18:57have. But we can expect
18:58this to increase even further
19:00because of the aging of
19:01the population, the screening tests
19:03that we have, early diagnosis
19:05for many different kinds of
19:06cancer.
19:08So how did we make
19:09these kinds of strides? Well,
19:11again, earlier detection,
19:13new drugs and other treatments,
19:15the advent of combined modality
19:16therapy, Prolonged adjuvant and or
19:19maintenance therapies have really played
19:20a role. And, again, in
19:21the case of breast cancer,
19:22because of our endocrine therapies,
19:24we see many
19:25fewer second cancers breast cancers,
19:28than we used to see.
19:30But think about all the
19:31patients who are living now
19:32long term on immunotherapy
19:34with melanoma
19:35and other cancers. So there's,
19:37again, a lot of therapy
19:38that patients are get getting
19:40that are leading to longer
19:41lives and survival, and then
19:43this prevention of second malignancies.
19:46But there is a cost
19:47and the cost is time.
19:49And if we think about
19:50it, when I started my
19:51career,
19:52patients say with breast cancer
19:54just had surgery, maybe they
19:55had radiation,
19:56they were in the hospital
19:57for a longer time with
19:58that initial treatment, they might
20:00have had a radical or
20:01a modified
20:01radical mastectomy.
20:03But it was kind of
20:04over with it, you know,
20:05six, eight weeks after their
20:06initial diagnosis.
20:08If you take a breast
20:08cancer patient today, it may
20:10be nine months to a
20:11year before she finishes any
20:13treatment if she has reconstruction
20:14and even has,
20:15more prolonged,
20:17targeted therapy.
20:18It may even go into
20:19two years. So a very
20:21long period of time, and
20:22that period of time really
20:24is kind of mirrored in
20:25the time of recovery.
20:27I did the quality of
20:28life recently for the OLYMPIA
20:30trial, which was just after
20:32adjuvant chemotherapy and BRCA one
20:34and two carriers, a PARP
20:36inhibitor for a year. And
20:38we expected that there would
20:39be recovery
20:41in the control arm that
20:42didn't get the PARP inhibitor
20:44by a year,
20:45because that's what we had
20:46seen in a lot of
20:47other, other,
20:48trials. But, no, even in
20:50the control arm, it was
20:51two years before fatigue,
20:54improved, in those patients. So
20:56the burden of our initial
20:57treatments now are much more
20:59substantial.
21:01So then, really, for many
21:03patients, cancer's now a chronic
21:05disease. It just, you know,
21:06maybe chronic in the sense
21:08of you are getting ongoing
21:09therapy, and I'll speak to
21:10people living with metastatic disease.
21:12But the sequelae in the
21:14after effects
21:15may not go away for
21:16a large number of people.
21:18And again, this is what
21:19we've been focused on studying
21:20in the last couple of
21:22decades.
21:23So
21:24just to kind of clarify
21:26some
21:27semantics, if you will,
21:29in general, we think about
21:30a long term effect as
21:32something
21:33that comes on during treatment.
21:35So it could be fatigue.
21:36It could be,
21:39cognitive
21:40difficulties. It could be mood
21:41changes, whatever, difficulties with sleep,
21:44and it just doesn't go
21:45away. You're seeing that person
21:46back. Normally, we expect people
21:48to have a recovery in
21:49the year after their treatment
21:50ends. But if it's persisting
21:52beyond that, it's really a
21:54long term persistent problem that
21:56came on associated with the
21:57treatment.
21:58In contrast, a late effect
22:00is something that crops up
22:01later kind of out of
22:02the blue. So the patient
22:04who goes into heart failure
22:05later or the patient who
22:07may have osteoporosis
22:08and that starts to have
22:09fractures later, things that really
22:11are not there that are
22:13immediate with the treatment. They
22:14tend to be rarer, but
22:15sometimes more serious and catch
22:17patients and doctors by surprise.
22:20But, again, it's difficult sometimes
22:22to kind of separate these
22:23things, and I don't really
22:24care if you call it
22:25a late effect or a
22:26long term problem. They're just
22:28the after effects of the
22:29cancer treatment.
22:32So this is actually a
22:33Yale publication from Michaela's group,
22:35which I I'm I'm a
22:37consultant on her ACS grant,
22:39and she but she this
22:40was some work that she
22:41and her team were doing.
22:42And they were looking at
22:43the NHIS,
22:45dataset, the National Health Interview
22:46Survey, and they were looking
22:48at what happened to patients
22:49in terms of self reporting
22:51about whether they have limitations.
22:53And if this is you
22:54can push or pull an
22:55object or do kind of
22:57heavy lifting, things around the
22:58house, these kind of functional
22:59limitations.
23:00And this is looking at
23:01the people who said they
23:02had a history of a
23:03cancer diagnosis.
23:04And we can see over
23:05time
23:06the numbers who are without
23:08limitation, maybe it's going up
23:09a little bit. But look
23:10at this between nineteen ninety
23:12nine and two thousand seventeen.
23:14And again, these are cross
23:15sectional. It's not longitudinal.
23:17But we can see the
23:18instantaneous reporting
23:19of people here now in
23:21two thousand seventeen. We have
23:22eight million of them roughly
23:24estimated from the population who
23:26are living with limitations from
23:27their cancer,
23:29associated with their cancer diagnosis.
23:31And here, if we look
23:31at again, this is the
23:33fold to to this is
23:34a two fold,
23:36two point two five fold
23:37increase,
23:38in, amount of limitations,
23:40that individuals with a cancer
23:42diagnosis and history of cancer
23:44are reporting. So this is,
23:45in fact, quantifying some of
23:47those things that I've told
23:48you that you can either
23:49hear about in your clinic
23:50or hear about in the
23:52reports that we wrote write
23:53about in terms of clinical
23:55trial results or in terms
23:56of observational studies.
23:59So,
24:00again, to show a little
24:01bit about what goes on
24:02in terms of how we
24:03look at the results of
24:04a clinical trial,
24:06this was an NSABP trial,
24:07the b thirty trial, which
24:09was a three arm randomized
24:10controlled trial,
24:12in higher risk breast cancer
24:13patients that had more advanced
24:15stage disease. And it was
24:16asking
24:17whether you needed to have
24:18a whole you know, an
24:20extended sequential,
24:21course of docetaxel, which is
24:23a taxane therapy in addition
24:25to adriamycin and cytoxin.
24:27But one of the arms
24:28actually eliminated the cytoxin.
24:30So there was a possibility
24:32that in some women, there
24:33might not be so much
24:34amenorrhea
24:35as a result of the
24:36treatment. And you might be
24:37able to have,
24:39potentially a better outcome in
24:40terms of,
24:42potentially having children or other
24:44effects. And so there's a
24:45difference in the docetaxel
24:47arms between these three, treatments.
24:49But if you can see
24:50the results of the trial,
24:52you know, these curves are
24:53pretty much overlapping,
24:55but the sequential therapy actually
24:57comes out to be a
24:58little bit better. You can
25:00see,
25:01that it's better.
25:02And,
25:03and if you ask the
25:05patient and you ask the
25:06doctors, everybody's thinking that we
25:08have to have the sequential
25:09therapy.
25:10And if you look at
25:11how the data are reported
25:13in the New England Journal,
25:14report, these are only grade
25:16three and four three to
25:17five three and four adverse
25:18events. You can see the
25:19sequential therapy, which has six
25:21cycles
25:22of the docetaxel.
25:24You know, you can see
25:25there's more neutropenia.
25:26There's more fatigue,
25:28you know, in terms of
25:29these kinds of problems.
25:30Neuropathy wasn't even mentioned here
25:32because it's not grade three
25:34or four. It's probably grade
25:35one or two. But if
25:36you treat anyone with a
25:38taxane regimen, you know that
25:39neuropathy is going to be
25:40a big problem for these
25:42patients, and that's going to
25:43be a burden for them.
25:45This was our companion quality
25:47of life study,
25:48for this particular,
25:49trial, and we were interested
25:51in whether there was a
25:52difference in amenorrhea
25:54between the two arms. But
25:55I just wanna point out
25:56the quality of life
25:58data. And these are data
25:59with the FACT trial outcome
26:01index, which is the physical
26:03and functioning scales of the
26:05the FACT and the symptom
26:06scale. And you can see
26:08that this blue line here
26:10is the sequential therapy. So
26:11here,
26:12six months of therapy is
26:13longer for these patients, but
26:15we have the other two
26:16arms kind of recovering. And
26:18everybody comes back to where
26:19they were at baseline. So
26:21if you look at overall
26:22quality of life and functioning,
26:24patients are actually doing okay.
26:26There's not much difference between
26:27the arms. But, again, if
26:29we look here
26:30now at symptoms, which was
26:32a summary of a symptom
26:33checklist, look, there's a a
26:34score of about ten for
26:36the severity of the and
26:37number of symptoms here at
26:38the beginning,
26:39and it's higher in the
26:41docetaxel
26:41arm where it's sequential.
26:43And they all come back
26:45down, but they're much higher
26:47than the patients were before.
26:48So you this is this
26:49persistence
26:50of symptoms that we're showing
26:52in a clinical trial. And
26:53again, the clinical trial is
26:54great because you can compare
26:55arms, but you also have
26:57a good data out to
26:58this point in time in
26:59a prospective way.
27:01So we decided to go
27:02back and look at neuropathy
27:03since that really hadn't been
27:05reported in the study.
27:06And again, looking here at
27:08baseline,
27:09patients are reporting a little
27:11bit of, this is either
27:12not at all zero, one
27:14a little bit, two somewhat,
27:16three quite a bit, and
27:16four on the severity scale.
27:18And so there's not much
27:19neuropathy at the at the
27:21beginning, but some people do
27:22have some. But again, the
27:23sequential arm has a lot
27:25more neuropathy here in terms
27:27of patient reported complaints. And
27:29if we look at everyone,
27:30they're still elevated out here
27:32at twenty four months. Again,
27:33a bit higher in the
27:35sequential arm, which has a
27:36higher dose.
27:38And then we went and
27:39looked at what were the
27:40predictors of having persistent symptoms
27:42over time. And this was
27:44what we were seeing in
27:45terms of whether you had
27:47baseline neuropathy. Those few patients
27:49who did have neuropathy at
27:50the beginning, again, asking about
27:52what people are functioning like.
27:54The treatment regimen, again, more
27:55taxane as you would predict.
27:57Being older was also highly
27:59significant in terms of the
28:01multivariate model. Greater nodal involvement,
28:04mastectomy,
28:05and greater BMI. So these
28:06are all what we call
28:07host factors that influence the
28:10persistence of neuropathy. So it's
28:11not just getting that sequential
28:13longer dose, higher dose,
28:15but also these host factors.
28:17And, again, very important. So,
28:19again, we did some qualitative
28:21data with both patients and
28:22doctors to see, would you
28:24ever modify your regimen based
28:26on these things?
28:27Patient said, no. I want
28:29the best therapy. If it's
28:30better, I want it. And
28:31the doctor said, well, I
28:32couldn't do anything that was
28:34off guideline. You know, if
28:35the guideline says this, and
28:36these were good oncologists both
28:38in the community and breast
28:40specialists at various
28:41institutions. So that was an
28:43interesting exercise.
28:44And again, just to show
28:45you here that the severity
28:47of the neuropathy actually influences,
28:50the quality of life. So
28:51this is the fact the
28:52trial outcome index, the quality
28:54of life measure. And we
28:55can see the higher the
28:56severity
28:57of the neuropathy, the poorer
28:58the quality of life. Other
29:00people have done studies again
29:01showing that there's a higher
29:02fall risk in people who've
29:04had taxanes,
29:05as part of their therapy.
29:07And so this becomes an
29:08ongoing problem that somebody needs
29:10to live with. And I
29:11don't even wanna go go
29:12there, but if we think
29:13about immunotherapy
29:15in patients who've become adrenally
29:17insufficient or have bad thyroid
29:19complications,
29:20others from the immunotherapy,
29:22these are things that the
29:23person might be getting curative
29:25adjuvant therapy,
29:26but then has the sequelae
29:27that we have to deal
29:28with. So we very much
29:30need to be concerned about
29:31these
29:33things. So this is, a
29:35way of now looking at
29:37what we're doing to patients
29:38in terms of the long
29:39term biological
29:41effects of the treatments that
29:42we provide. And a lot
29:43of the work that our
29:44our group has been focused
29:45on has also been accelerated
29:47aging. This is a nice
29:48review paper that Mina Sedrick
29:50wrote, several years ago. He's
29:52now been recruited to UCLA
29:54and as part of our
29:54group. But, again, thinking about
29:57the fact that we are
29:58exposing people to all of
29:59these kinds of therapies,
30:01and it's great for the
30:02cancer cells, but it's not
30:03so great for the normal
30:04tissues in terms of the
30:06injury that we,
30:07provide to those tissues. If
30:09you want, you can think
30:10about them as off target
30:12experiences.
30:13And these all lead to
30:14increased inflammation in the body
30:16and the potential for accelerated
30:18aging. And so we need
30:20to think about a subgroup
30:21of patients who may have
30:22these long term problems. Now
30:24the most classical subgroup for,
30:26like, thinking about this are
30:27the childhood cancer survivors,
30:29who we now have thirty,
30:30forty, fifty years of follow-up
30:32showing that they are all
30:33dying at an earlier age.
30:35They have comorbidities
30:36that you would expect with
30:37much older patients and have
30:39the frailty phenotype where people
30:41have fatigue,
30:42difficulty doing physical activities, and
30:44so forth, and are impaired
30:46as a result of this.
30:47And in cancer, when we
30:49were only treating people in
30:50our sixties, seventies, and eighties
30:52where they might not live
30:53long enough to have these
30:54kinds of problems,
30:55some of us who've been
30:56interested in younger adults with
30:58cancer are very worried because
31:00they have no other risk
31:01factors other than the cancer.
31:02We're treating them intensively
31:04and we may are beginning
31:05to see accelerated aging in
31:07these individuals who are now
31:08living a longer time with
31:09the after effects. So we
31:11really need to be thinking
31:12about cure,
31:13but we need to be
31:14cognizant
31:15of the potential long term
31:17and late effects that may
31:18be occurring. And it would
31:20be wonderful if we could
31:21really figure out who's most
31:22susceptible so we could, in
31:23fact,
31:24personalize this and do this
31:26more precisely.
31:27So the chronic symptoms that
31:29I've told you about in
31:30adult cancer survivors, such as
31:32fatigue,
31:33cognitive difficulties, neuropathy, pain, decreased
31:36physical functioning, insomnia.
31:38These are all classically things
31:40that are very common in
31:42aging. And if any of
31:43you have had aging parents
31:44or know of individuals
31:46who you've watched go through
31:47this, you know that the
31:48frailty phenotype
31:50as people go unless they
31:52die suddenly as an older
31:53person. But usually, there's a
31:54gradual decline in function, and
31:56we are seeing this now
31:57in patients who are much
31:59younger who have been treated
32:00for cancer
32:01with these symptoms as being
32:02part of the manifestation.
32:04So I've been very fortunate.
32:06About twenty five years ago,
32:08doctor Julie Bauer came into
32:09my lab as a postdoctoral
32:11fellow, and doctor Mike Erwin,
32:13who's a psychiatrist,
32:15relocated to Los Angeles from
32:16the UC UC San Diego
32:18and, to be the director
32:19of the cousin psychoneuroimmunology
32:21center.
32:22And he really had been
32:24very innovative with other people
32:27looking in the laboratory with
32:28better ways to look at
32:29inflammation. And, again,
32:31if we think about the
32:32advances that have been made
32:34in measuring all sorts of
32:35things, he brought that science
32:37to UCLA
32:38and our ability to look
32:39at this. And this review
32:40paper that was written in
32:41JCO,
32:43in two thousand eight with
32:44other colleagues really focused fact
32:47that the tumor, the metastases,
32:49chemotherapy, all of the things
32:50that we did to patients
32:51here on the left, that
32:53the patient came to us
32:54with and we did to
32:55them on the left hand
32:56side had a dramatic effect
32:58on the neuroendocrine system,
33:01really through inflammation
33:03primarily
33:04and interfering with sleep and
33:06having all sorts of effects
33:07on the central nervous system
33:09leading to the behavioral alterations
33:11that you see on the
33:12right,
33:13such as depression, fatigue, impaired
33:15sleep, and cognitive dysfunction. And,
33:17again, this gave us the
33:18biological
33:19underpinnings, if you will, for
33:21understanding some of these symptoms.
33:23So again, I was very,
33:24very fortunate. And our group
33:26has really looked at all
33:27of these symptoms in a
33:28variety of studies.
33:30So just again, for those
33:32of you who may not
33:33see patients who are, complaining
33:35of this in the clinic,
33:36to tell you what a
33:36patient describes to us. This
33:38was actually a a phys
33:39a physical rehabilitation
33:41physician with breast cancer who
33:43said, during cancer therapy, I
33:45also always felt the exhaustion
33:47of physical exercise
33:48without any of the positive
33:50physical attributes.
33:51My limbs felt heavy. The
33:53quality of my sleep was
33:54changed. The mere act of
33:56sleeping itself seemed like work
33:58sometimes.
33:59My brain felt tired and
34:00so did my spirits. I
34:02seem to have lost my
34:03zest for life. So I
34:04think, you know, this really
34:05encapsulates
34:06all of those symptoms. And
34:08when I used to see
34:08these patients initially, in fact,
34:10one of my colleagues who
34:11was diagnosed with breast cancer
34:13and had these symptoms, they
34:14looked depressed. And you you
34:16you, you know, just kinda
34:17say, why don't you get
34:18on with your life? You
34:19know, what's going? But they're
34:20really sub suffering and symptomatic.
34:23And now that we've all
34:24lived through COVID and long
34:26COVID, this is what's going
34:27on in long COVID. And,
34:29my, again, interpretation of what
34:31we see with the inflammation
34:33associated with COVID is that
34:34the body only has a
34:36certain repertoire
34:37of how to respond to
34:38an acute inflammatory challenge, and
34:41that's what we do with
34:42cancer treatment. Whether it's radiation,
34:44chemotherapy, putting all of these
34:46things together, we're dealing with
34:47an acute inflammatory,
34:49challenge. And again, this is
34:51how the body responds
34:52with an increase in pro
34:54inflammatory cytokines.
34:55And there may be local
34:56and systemic effects,
34:58including all of these cytokines
35:00affecting the central nervous system
35:02where in fact you can
35:03see both the brain symptoms
35:05and the fatigue really being
35:07influenced
35:08by inflammation. And we've been
35:09able to document this in
35:10a quite a bit of
35:11our work. One of the
35:12first studies was that, doctor
35:14Bauer actually followed up on
35:15the patients,
35:16that we had recruited
35:18in our sexuality and intimacy
35:20study. We had a couple
35:21thousand patients where we had,
35:23all these kinds of questions
35:24asked about them before we
35:25went into an intervention.
35:27And she was able to
35:28recruit some of these patients
35:29to come back into the
35:30lab and actually test them
35:32and evaluate them and actually
35:34show that there were changes
35:35with inflammation and bringing that
35:36into our lab. But things
35:38that are associated with fatigue
35:40in our cancer survivors and
35:41breast cancer survivors are the
35:42comorbid medical conditions. So again,
35:44things that are also,
35:46going on in the host.
35:48Increased body mass index,
35:50anemia is very rare.
35:52But demographic factors, younger age,
35:55lower income,
35:56not being married,
35:57or living with someone is
35:59important.
35:59Psychological factors, a past history
36:02of depression,
36:03a catastrophizing
36:04coping style, but good things
36:06being physical activity, so inactivity
36:08not being good. And then
36:09these comorbid symptoms that were
36:11often co occurring
36:13with fatigue, such as pain,
36:14menopausal symptoms, and sleep disturbance.
36:16A lot of these things
36:18all associated with inflammation.
36:20And in the early studies
36:21that she did, she was
36:22able to document higher levels
36:24of inflammation in the patients
36:26who were more fatigued. And
36:27this was going out five
36:28years and then subsequently eight
36:30years out after their initial
36:31questionnaire data.
36:33And, again, in many works
36:35that she's written,
36:36again, this is one review
36:38a number of years ago,
36:39really looking at host factors
36:41that are associated with this
36:43and ways that we might
36:44begin to intervention to intervene
36:46on this. And, doctor Bauer
36:48actually led the ASCO,
36:50guideline fatigue,
36:52guideline on fatigue,
36:54in two thousand thirteen. And
36:55we just updated it now
36:56where she again,
36:57led this, as well. So
36:59if you're interested, you can
37:00read about the recommendations
37:02how we manage fatigue in
37:03cancer survivors.
37:05But I just wanna show
37:06you about how we might
37:08be able to get a
37:08little bit more precise
37:10in terms of understanding why
37:12some individuals might be more
37:13predisposed
37:14to have preexisting fatigue.
37:16This was in a study,
37:18it was our mind body
37:19study where we recruited women
37:21who were just about to
37:22initiate endocrine therapy and we
37:24were following them for cognitive
37:26difficulties over time. But this
37:27was from the baseline data
37:29where we looked at fatigue
37:30and cognitive complaints in these
37:32patients and looked at snips
37:34in the promoter regions of
37:36TNF
37:37alpha IL six and IL
37:39one to see if there
37:40was any genetic predisposition
37:42to have a more a
37:44greater inflammatory
37:45response and symptoms.
37:47And here what we're showing
37:48is with the MFSI
37:49fatigue score, patients with the
37:51GG
37:52genotype of TNF,
37:54three zero eight, have a
37:55higher reporting of fatigue. You
37:57can see the AA
37:59SNP has a very low
38:00reporting. Here, if we look
38:01here at IL six, the
38:03SNP, the GG,
38:05pattern has a higher reporting
38:07of fatigue. And here, this
38:08is the CC SNP of
38:09IL one. So you can
38:11see that there's variation
38:13based on the genetic,
38:15components in a person's makeup.
38:17You know, these are not
38:18abnormalities. It's just how they
38:19might be handling potentially inflammation
38:22in their body. And this
38:23was true for both cognitive
38:24complaints and fatigue at baseline.
38:28In addition,
38:29we put together an additive
38:31genetic score. So the more
38:32of these,
38:33SNPs that you have that
38:35are the higher burden SNPs
38:36in terms of inflammation,
38:38the greater the reporting of
38:40fatigue you can see in
38:41terms of the score. And
38:42in a multivariate
38:43model,
38:44predictors of fatigue were age,
38:46body mass index,
38:48whether you got chemotherapy or
38:49not, or the genetic risk
38:50score. So, again, these host
38:52factors
38:53that may be giving us
38:54a clue as to who
38:56may be more at risk
38:57for symptoms and if we
38:58could, in fact, use this.
39:00Now I have to say,
39:01we haven't completely validated this.
39:03We have a new,
39:04study actually where we're one
39:06of the clinical trials that
39:07we're looking at, maybe even
39:09BIOSHA's fourteen eighteen trial,
39:11that he was just asking
39:12me about analyzing,
39:14where we may be able
39:14to replicate this data.
39:17So,
39:17doctor Bauer recently did another
39:19study where we wanted to
39:21understand
39:22how did people, you know,
39:24with all of our other
39:24data had been cross sectional.
39:26How did they get there?
39:27Did they have fatigue in
39:28the very beginning, or did
39:30it sometime come off on
39:31with treatment? And so this
39:33was an inception cohort of
39:35patients who had not yet
39:36gotten their chemotherapy treatment. They
39:38had had surgery but had
39:39not had radiation.
39:41And if we look here,
39:43we can look at the
39:44baseline,
39:45which is over here on
39:46the left, and you can
39:47see a few of the
39:48people here. This is a
39:50cohort of a little over
39:51two hundred patients.
39:53A few of them had
39:53high levels of fatigue on
39:55the MFSI,
39:56but most of them here
39:57in the green had stable
39:59low, hundred and seventy eight
40:00out of these two hundred
40:01and seventy patients had low
40:03scores, and they never actually
40:04rose. But if we look
40:06at eighteen months over here,
40:08which is where we might
40:09do a cross sectional analysis
40:11of patients, so these are
40:13people who have somewhat elevated
40:15levels. And you can see
40:16some of them were actually
40:18low to begin with. Some
40:19of them were high and
40:20actually declined and even didn't
40:22have high levels. And then
40:23some who were persistently high.
40:25So understanding,
40:26again, we've done a lot
40:27of analysis of this data,
40:29but there are a number
40:30of psychosocial predictors. And I
40:32was mentioning to someone last
40:33night, early childhood trauma is
40:35actually a predictor in some
40:37of these individuals for having
40:39high levels of fatigue and
40:40other symptoms at baseline
40:42that actually persists. So that
40:44could be something we might
40:45wanna be able to incorporate
40:46into our evaluation.
40:49So why is it under
40:50important to understand biological mechanisms
40:53of the treatment?
40:54I can't tell you how
40:56validating this is for patients.
40:58People look me up on
40:59the web or they've heard
41:00me talk, etcetera.
41:02And when I can say
41:03to them, there's a biological
41:04reason why you're still having
41:06fatigue or cognitive complaints, they
41:08feel much better. It doesn't
41:10take away the symptoms, but
41:11it means that they really
41:12have something. It's not just
41:14in your head,
41:15literally and figuratively.
41:17And so that's very valuable.
41:18In addition, it really helps
41:20us to develop interventions,
41:22either pharmacological or behavioral. And
41:25we've now done a lot
41:26of behavioral interventions where we
41:27actually show we can move
41:28the needle on the inflammation,
41:31and it is actually associated
41:32with the response, the clinical
41:34response to treating those symptoms.
41:36And possibly, we might be
41:37able to identify people who
41:39are at higher risk. And
41:40there may be some concerns
41:41about how this inflammation is
41:43also affecting tumor biology and
41:45prognosis for patients. So there's
41:47a lot going on here,
41:48but understanding this, I think,
41:50is very powerful.
41:52So, this is a review
41:53that we wrote recently that
41:54talked about some of these
41:55things. And if you're interested,
41:57you may wanna look at
41:58this. But, it's incorporating these
42:00issues of accelerated aging, persistent
42:03inflammation,
42:04and looking at interventions, behavioral,
42:06and potentially pharmacologic
42:08that might be useful. And
42:09I'm really I'm just completed
42:11a phase two trial of
42:12a very interesting nutraceutical
42:14that seems to be actually
42:15very effective
42:16in decreasing cognitive complaints in
42:18women with breast cancer. And
42:20we're actually now going back
42:21to the clinic and doing
42:22a mouse model to see
42:23if we can actually show
42:24the biology of how I
42:26think we're decreasing neuroinflammation.
42:28So these are very important
42:30things to really understand to
42:32improve the well-being of our
42:33patients.
42:34I wanna just spend the
42:35last few minutes talking about
42:36a couple of special populations
42:38that we need to think
42:39about and for future research,
42:40people who are now in
42:42this field to think about.
42:43And that's the young adult
42:44cancer patients and survivors and
42:46people living with metastatic disease.
42:49So again,
42:50this is a minority group,
42:52if you will, within the
42:53two million cancer,
42:55cases that are diagnosed every
42:56year, but very important.
42:58And,
42:59it's again challenging
43:00because young adults have heterogeneous
43:02cancer diagnoses. You know, it
43:04ranges from leukemia,
43:06people who are getting, transplanted
43:07in
43:15think about cancer in a
43:15young person, plus we don't
43:16think about cancer in a
43:17young person, plus we don't
43:19screen for cancer. Again, we've
43:21just now moved the colorectal
43:22cancer screening guidelines down to
43:24forty five, but a lot
43:25of them are being diagnosed
43:26when they're thirty five. The
43:27breast cancer patients are being
43:28diagnosed. They come in with
43:30a lump, nobody pays attention
43:31to it, or it's post
43:32pregnancy,
43:34that they may have this.
43:34And so, again, there's a
43:36good reason why they often
43:37have, more advanced disease. They
43:39get more toxic therapy mostly
43:41because we've thought that we
43:42they can tolerate it, and
43:43we wanna treat them for
43:45cure.
43:45So that's very important. A
43:47lot of them are uninsured,
43:48so that's a big issue.
43:49It's their first encounter with
43:50the health care system. And
43:52so the
43:53financial toxicity
43:54is very, very high. And
43:56already, this segment of the
43:57population has high rates of
43:59anxiety and depression
44:00just in the background before
44:02they ever get cancer and
44:03is exacerbated with this. So
44:05again, very disruptive to young
44:07people. And it's not the
44:08same for a twenty year
44:09old as it is for
44:10a thirty five or a
44:11forty five year old. So,
44:11again, there are different age
44:13and developmental stages in this
44:15group that we have to
44:16pay attention to. But I
44:17wanna call you attention call
44:19your attention to this particular
44:20study,
44:21that was con
44:22commissioned by Teen Cancer America,
44:24really looking at the cost
44:25of cancer care and not
44:27just the economic cost, the
44:28financial cost, but also the
44:31lost employment and opportunities,
44:34other things that happened to
44:35them,
44:36loss of well-being. And I
44:37just again, it's a dense
44:38slide. But I wanna just
44:40pull out here,
44:41the age thirty five to
44:43thirty nine and look at
44:45this is men here and
44:46this is women and this
44:47is the total in millions
44:49in terms of of cost.
44:50And there's this big difference
44:51here, and this is probably
44:52driven by the breast cancer
44:54cases where, again, very common
44:56disease in this age group,
44:58but for women having more
45:00burden here.
45:01And then if we look
45:02at
45:03I wanna just say the
45:04health system costs here, the
45:06cost per person per
45:08thousand is thirty five thousand
45:09if we just look at
45:10the health system costs, but
45:11the productivity costs are a
45:13hundred and ninety nine per
45:14person. But if we look
45:15at the financial total financial
45:17costs overall,
45:18it's two hundred and fifty
45:20nine thousand per person. And,
45:22again, in terms of burden
45:23of disease, in terms of
45:24the non financial,
45:26over a million. So again,
45:27this is looking at a
45:28lifetime,
45:29perspective. So we do need
45:31to pay attention to these
45:32younger adults,
45:33with cancer.
45:35And then finally, coming to
45:36the people living with metastatic
45:38disease, this is a very
45:39large and growing number,
45:40in our clinics.
45:42We are very fortunate now
45:43to have had targeted therapies
45:45and serial targeted therapies or
45:47immunotherapies that have been very
45:48effective.
45:49And, it's very valuable to
45:51be able to take care
45:52of these patients, but they
45:53never go off therapy. It's
45:54very costly for them. There
45:56may be chronic morbidities.
45:57And, again, chronic myelogenous leukemia,
46:00which was kind of the
46:00poster child for this group
46:02of patients,
46:03very,
46:04important. They do have chronic
46:06fatigue as an issue. It
46:07could be a burden in
46:08terms of their being adherent.
46:09And so finding ways either
46:11to take them off their
46:12therapy, people are looking at
46:14minimal or residual disease, a
46:15lot of other things, as
46:16well as mitigating these, toxicities.
46:19So very important for us
46:20to think about them. And
46:22there was a a good
46:23study done, a few years
46:24ago,
46:26by, folks at the NCI
46:27calling out, in this case,
46:29bladder, breast, colon, rectum, lung,
46:31and bronc, lung cancer, melanoma,
46:34and prostate. So here's lung.
46:35And looking at the number
46:36of people living,
46:38with, lung cancer that have
46:40metastatic disease, you can see
46:41the large numbers here. And,
46:43recurrence as well. The dark
46:45blue is recurrent and de
46:46novo is the light blue.
46:48And you can see again
46:49for breast, we have a
46:50lot of recurrence, but we
46:51also have de novo going
46:53on here. So these are
46:54important diseases that we need
46:56to pay attention to because
46:57people are on long term
46:58therapy.
47:00And if you look at
47:01the length of time, the
47:02green boxes here are out
47:03to ten years. So this
47:04is the prostate cancer patients,
47:07melanoma,
47:08greater than ten years,
47:10colon and rectum and so
47:11forth. So these individuals are
47:13living a long time on
47:15chronic therapies very often,
47:17and so the financial burden
47:19and the morbidity from therapies
47:20need to be think think
47:21we need to think about.
47:23And this is a very
47:23hot and new area for
47:25people who wanna work in
47:26survivorship
47:28research. So I'll just close
47:29in the last few minutes
47:30about how we might think
47:31about survivorship research and survivorship
47:34care. And this is from
47:35the Institute of Medicine lost
47:37in transition report, and it
47:39may not be a perfect
47:40diagram of what goes on,
47:41but often we're treating people
47:42out here for cure. And
47:44this is the group of
47:44people who are living a
47:45long time. And this is
47:47where we can focus our
47:48attention in terms of research.
47:50So, again, in terms of
47:52research, we can think about,
47:54developing and evaluating treatments to
47:56improve quality of life or
47:57quality of care.
47:59We need to focus on
48:00preventing the late effects as
48:02I've already talked about, and
48:03we need to attend to
48:04the vulnerable populations
48:06and those with comorbid and
48:07conditions and who are disadvantaged.
48:09And we've spent a lot
48:10of time in the last
48:11few years about talking about
48:13the integration of palliative care
48:15with
48:16metastatic disease from the time
48:17of diagnosis because of the
48:19benefits. But palliative care is
48:20something that we actually need
48:21to do in every cancer
48:23patient and every survivor because,
48:25really,
48:26symptom management, as I've tried
48:27to emphasize,
48:28is very powerful. If you
48:30can control those symptoms, patients
48:32are gonna have higher levels
48:33of function, and they're going
48:34to be able to do
48:35better over the long haul.
48:36So thinking about palliative care
48:38again for everyone who's treated
48:40with cancer and particularly for
48:42survivors is very important.
48:44This is a nice, diagram,
48:47from folks at MD Anderson
48:48really kind of thinking about
48:49the continuum of care. And
48:51we can call it palliative
48:52care. We can call it
48:53supportive care. But all of
48:55those things that we give
48:56to people at the end
48:57of life, we should be
48:58giving right from the very
48:59beginning and really trying to
49:01highlight those most in need
49:02by screening, if you will,
49:04for symptoms and morbidities that
49:06people are having.
49:07So,
49:08in thinking about the kinds
49:10of study designs you might
49:11wanna consider in your symptom
49:13science research,
49:14Again, randomized controlled trials are
49:16really important in terms of
49:18evaluating,
49:19treatments. And I've been very
49:20fortunate because of my work
49:21in the,
49:22cooperative groups, but also even
49:24in our own, studies where
49:26we've either done attention control,
49:28wait list control, or placebos
49:29where you can kind of
49:30catch the natural history of
49:32the condition and then look
49:33at your intervention.
49:34But
49:35observational studies are also very
49:37powerful, and you can do
49:39a lot more data collection
49:40sometimes in your observational research,
49:42particularly collecting the data, the
49:44biological specimens, and more enriched
49:47questionnaires.
49:48Intervention studies are also very,
49:50very powerful because if you
49:51see an effect from your
49:52intervention,
49:53it can also show a
49:54biological marker moves with that.
49:56That again validates that. All
49:58the things that we would
49:59think about in terms of
50:00a therapeutic trial, we wanna
50:01do with these kinds of
50:02interventions.
50:03And then doing correlative studies,
50:05as I've mentioned, looking at
50:07animal models if we can
50:08use them to actually understand
50:09the mechanisms by which either
50:11drugs work or how the
50:13symptoms occur.
50:15Some additional observations. Well, again,
50:17clinical trials that include symptom
50:19assessments
50:19can identify target symptoms in
50:21need of our attention that
50:22we might not know about.
50:24We need to understand the
50:26treatment emergent as well as
50:27persistent post treatment symptoms.
50:30And we need to have
50:31effective management for symptoms in
50:33in in addressing adherence. Again,
50:36increasingly, we know that patients
50:37who have more symptoms, who
50:39have more social determinants of
50:40health difficulties
50:42are likely to be nonadherent
50:44to their therapy, which could
50:45be life saving.
50:46And, again, looking at research
50:48which focuses
50:50who's at greatest risk would
50:51be the most efficient way
50:53to do this. So defining
50:54those populations, developing
50:56precision symptom management would be
50:58very valuable.
51:00And understanding the biology, again,
51:02as I've emphasized, again, the
51:03good fortune I've had to
51:04have good collaborators to do
51:06this is very powerful.
51:09So what are some of
51:09the challenges and opportunities?
51:11Well, funding sources for symptom
51:13related research are limited,
51:15and assembling a multidisciplinary
51:17team might be difficult. Again,
51:19in
51:19a cancer center like yours
51:21or mine, this is a
51:22lot easier to do. And
51:23certainly being on a university
51:25campus is very helpful. And,
51:26again,
51:27comprehensive assessments that I've had
51:29the real privilege of doing
51:31over my career,
51:32can be very daunting. So
51:34it may not be easy
51:35to do this.
51:36But the growing number of
51:37cancer survivors
51:38really tells us that we
51:40cannot ignore this anymore. And
51:42it's really, you know, just
51:43as we're trying to figure
51:44out what's going on with
51:45COVID with millions of people
51:46now having long COVID, we
51:48have eighteen million cancer survivors.
51:51We need to be doing
51:52this for our cancer survivors
51:53as well.
51:55And lastly, I wanted to
51:56show this nice, editorial that,
51:58some of our colleagues in
52:00France who've been studying the
52:01Canto cohort. It's a cohort
52:03of breast cancer patients about
52:05ten thousand.
52:06Really, they are now, also
52:08again, we've collaborated with them,
52:09but they're really looking at
52:11systemic inflammation and cancer related
52:13frailty
52:13to kind of look at
52:14how we might put this
52:16into our clinics in the
52:17future with precision,
52:19identification of those at risk
52:20and need of treatment.
52:22So in closing, I wanna
52:24express my appreciation to everyone
52:26who's helped me along the
52:27way. This is not a
52:28solo act.
52:29I've had wonderful collaborators as
52:31well as patients who've been
52:32very, very important.
52:34I'll also the funding that
52:36I've had over, my career.
52:38And I wanna thank you,
52:39and I'll be happy to
52:40take some questions.
52:49Yes.
52:50Doctor Sam.
52:51Wonderful talk. It's been so
52:53inspiring.
52:54Let me grab the microphone.
52:58So you have this wonderful,
53:00experience and and advantage. In
53:02your in your view, looking
53:04ahead ten years,
53:05things are better for our
53:06patients.
53:08What are the main things
53:09that have happened to make
53:10that come true? Do you
53:12think it's de escalation
53:14or
53:15earlier interventions
53:16or better
53:17post treatment interventions for those
53:19types of symptoms? Oh, maybe
53:21we could get the lights
53:21back. So,
53:23This is the dramatic portion
53:24of our morning. So,
53:27so, you know, I think
53:29if changing anything, taking away
53:31something is very, very hard.
53:32Right now, we have a
53:33few deescalation trials,
53:35in NRG oncology
53:37in breast cancer. And,
53:39you know, we've
53:41perhaps in prostate cancer with
53:43active surveillance are are reducing,
53:45the treatments that patients would
53:47get treatment with. But it's
53:49so hard to sell this,
53:50and it's really hard in
53:51the medical community
53:52where it's hard not to
53:53treat. And it's also hard
53:55for patients and particularly with
53:57our minority underserved
53:59populations where they feel that
54:00the health system has cheated
54:01them and hasn't helped them,
54:03you know, in the past.
54:04And if we're trying to
54:05kind of say, well, you
54:06know, your tumor is so
54:08favorable that you really don't
54:09need this, it's a hard
54:10sell for things. And because,
54:12again, the American psyche I
54:14don't know whether they can
54:15probably do it better in
54:16Europe and a lot of
54:17countries, but our psyche is
54:18to treat.
54:19And even when you think
54:20about the troubles we had
54:22with managed care health care,
54:24people feel that they're being
54:25denied something in our system.
54:27And so it's very, very
54:28tough. I don't know if
54:29we can change our culture.
54:30I think that's the big
54:31challenge, Bios.
54:34So Betty, this is a,
54:36somewhat provocative question that I've
54:38been thinking about after I
54:39read an article in the
54:40New England Journal of Medicine,
54:42I think last year, and
54:43it was titled a nocebo
54:45effect.
54:47And I just wonder if
54:49some of this is related
54:50to our
54:51the way we we describe
54:53these drugs as horribly toxic,
54:55and people really look for
54:56the side effects.
54:58And many of the things
54:59that patients describe, unfortunately,
55:01I experience as I get
55:03older. The lack cramps, the
55:05back pain, and so forth.
55:06And I attribute it to
55:08my age because I don't
55:09take any drugs. But So
55:10it's not when you take
55:11the drug, you actually didn't
55:12take it. Yeah. Let me
55:12tell you about an interesting
55:14story.
55:16So I have a part
55:17I'm part of a u
55:17o one, which is looking
55:19at tolerability.
55:20Some move with a moonshot
55:21grant. We're in the last
55:22few months of it. And
55:23we are going back and
55:24looking at the p one
55:25data, the BCPT.
55:27We're gonna show you the
55:28data in the healthy women
55:29before they ever started anything.
55:31And we're,
55:32Lynn Lynn Henry and I,
55:34we got, additional using some
55:35of our BCRF money to
55:37look at the SNPs at
55:38rapid metabolizers of, CYP two
55:40d six to see if
55:42more toxicity is actually occurring
55:44in this particular trial. But
55:45we've begun to look at
55:46the tamoxifen versus placebo arm
55:48with the statisticians we've been
55:50working with. And when we
55:51looked at discontinuation of therapy
55:53in the randomized trial, again,
55:55placebo versus tamoxifen,
55:57we actually found that there
55:58was actually seemed to be
55:59no difference when we kind
56:00of looked at overall toxicity.
56:02And then as we began
56:03to explore things, I'm just
56:04looking at the nocebo effect
56:06in the control arm. And
56:08what we see is in
56:09the patients who got placebo,
56:12they have an increase in
56:13their hot flashes at three
56:14months.
56:15It kinda stays steady at
56:17six months. It doesn't go
56:18up. In the treatment arm,
56:19it's higher. The the odds
56:21ratio for hot flashes
56:23being elevated at three months
56:24is higher in the treatment
56:25arm with Tamoxifen and goes
56:26up further. And it's particularly
56:28marked in the women who
56:29are less than fifty and
56:30fifty to sixty,
56:32whereas in the
56:33placebo arm, it's in all
56:35age groups. So I'm gonna
56:36write a paper on this
56:38nocebo effect because
56:39for me, this was fascinating
56:42to see
56:43that, in fact, I mean,
56:44everybody moxifen had a bad
56:46rap. It was a cancer
56:47drug. Why you're giving a
56:48cancer drug to prevent cancer
56:50in, you know,
56:51healthy women. But I I
56:53think our placebo
56:54trials,
56:55will have a chance to
56:56look at this issue. And
56:57I'm just, again, fascinated by
56:59the fact that we're seeing
57:00this. Yeah, it's really interesting
57:02what you said, because we
57:03actually saw the same thing
57:04in, in a number of
57:05randomized trials, adjuvant trials in
57:07swag that we never published,
57:09that in the control arm,
57:11people who discontinue the placebo
57:13for whatever
57:14pill they were taking us
57:15in the active arm
57:17actually do worse in the
57:19control arm than those who
57:20don't discontinue
57:21the placebo. And we're looking
57:23at some of these predictive
57:24factors. You know, we'll look
57:25at we're actually starting to
57:25do the longitudinal models, but
57:26absolutely. And when I just
57:26recently went to the literature
57:27to look at the nocebo
57:27effect in cancer, I couldn't
57:30find much. So
57:34I couldn't find much. So
57:35I feel compelled to write
57:36this up because, again, here's
57:38healthy women. They're not people
57:39with cancer.
57:40And, of course, they're at
57:42an age group where they
57:43could have all of these
57:43symptoms together,
57:45but it's very you know,
57:46I had women when I
57:47was treating people on p
57:49one who quit you know,
57:50when we,
57:51divulged what treatment arm they're
57:52on, they were so upset
57:53that they were on placebo
57:55because they had attributed
57:56all of their sexual difficulties,
57:58whatever it was to the
57:59fact that they were on
58:00Tamoxifen, and they were very
58:01angry. It was very interesting.
58:02Really in charge of the
58:04health situation. Yeah. Yeah. Yeah.
58:05So but it's excellent question.
58:08Yeah. Thanks, Patty, for a
58:08wonderful talk. I was struck
58:09by the number of lung
58:10cancer patients living with metastatic
58:12disease. It reminds me, maybe
58:13twenty five years ago, twenty
58:14three years ago, Tara Parker
58:15Pope write an article why
58:17curing your lung cancer might
58:18be the best thing and
58:19the idea that people could
58:20live with these targeted therapies.
58:22And we just had the
58:23twentieth anniversary
58:24of EGFR mutations, and we
58:26had a symposium here at
58:26Yale a few weeks ago.
58:27And probably very few people
58:28are cured on these targeted
58:29therapies, but they're living with
58:30them. And now as we're
58:31moving to earlier disease, it's
58:33important to keep them on
58:33the drugs. So my question
58:35is about access and how
58:36with the entire country or
58:37world, how do we get
58:39patients the the right symptom
58:40relief? Can we use telehealth?
58:42You know, I'm frustrated we
58:43can't even do telehealth anymore
58:45from here, you know, across
58:46state lines. Are there processes
58:48in place where people could
58:49get both symptom relief and
58:50support, and they also need
58:51emotional support? And how are
58:52we gonna get all diverse
58:53populations this access? Yeah. I
58:55I think that is the
58:56next question.
58:57When I was at ASCO,
58:59I was impressed in the
59:00sessions that I went to
59:01where people are now trying
59:02to incorporate pros
59:04into monitoring of patients.
59:06There are major challenges in
59:07trying to be able to
59:09deliver this. And whether it's
59:10gonna be navigators
59:12or telehealth, I think this
59:13is the next group of
59:14interventions that we need to
59:15test and show they're cost
59:17effective
59:18as well as, effective in
59:19terms of benefit for patients.
59:21And we need to be
59:21able to do that outreach.
59:22And absolutely and for some
59:24things, we don't have a
59:25lot of symptoms. I mean,
59:26I can tell you I
59:27can tell you a a
59:28range of things you can
59:29do for fatigue that are
59:31non drug related.
59:33You know, tai chi is
59:34very effective for insomnia. When
59:36I speak to communities, it's
59:37very hard to get CBTI
59:39for insomnia. It's, you know,
59:40it's probably not even easy
59:42here in your cancer center
59:43to get that, but you
59:44tai chi is effective. Acupuncture
59:46is effective. And in many
59:47communities,
59:48these are available. But our
59:50community of physicians
59:51doesn't actually know a lot
59:52about these behavioral interventions. And
59:54that's why the ASCO guidelines
59:56are very powerful. If you
59:57look at the ASCO,
59:58fatigue guideline,
59:59exercise is very important.
01:00:01Mindfulness is very effective. Cognitive
01:00:04behavioral therapy, there are a
01:00:05whole bunch of therapies
01:00:06that, again, are not costly
01:00:08in terms of, you know,
01:00:09how we think about the
01:00:09cost of our drugs, but
01:00:11you need to be able
01:00:12to connect people. And a
01:00:13lot of these things are
01:00:14now available online, so it's
01:00:16kind of cataloging them and
01:00:17connecting patients. But I think
01:00:18we need to do high
01:00:19level randomized trials to show
01:00:21the evidence so that we
01:00:23can get payers to pay
01:00:24for these things.
01:00:26Because, you know, one of
01:00:27my sadnesses
01:00:28is that we all do
01:00:29these randomized trials, get NCI
01:00:32funding to show something's effective,
01:00:34but they're not disseminated.
01:00:36Anne Partridge,
01:00:37Antonio Wolf, and I did,
01:00:39and Julie Bauer did a
01:00:40study on, mindfulness and survivor
01:00:42education in younger women with
01:00:44breast cancer,
01:00:45and we found that it
01:00:46was the mindfulness in particular
01:00:48was very effective.
01:00:49Very fortunate that we just
01:00:50got an r o one,
01:00:51and we're putting it into
01:00:52an NRG trial
01:00:54to be able to disseminate
01:00:55now mindfulness
01:00:56either with an app or
01:00:58on Zoom,
01:00:59delivery,
01:01:00across the country, hopefully, to
01:01:02rural and underserved populations as
01:01:04well as, you know, the
01:01:05cancer center kinda people will
01:01:07come on. You could add
01:01:08that that Lomap trial, like
01:01:10the pragmatic arm, you know,
01:01:11and you can grab large
01:01:13amounts of data.
01:01:14Yes. And, I mean, I
01:01:15think if you have descriptions
01:01:17of what people are experiencing,
01:01:19then you have that catalog
01:01:20of list of issues, and
01:01:22then you link it up
01:01:23with resources that are available.
01:01:25And more and more, they
01:01:26can be on a centralized
01:01:27portal somewhere.
01:01:29I I when I was
01:01:30at VCU a couple weeks
01:01:31ago, one of the, people
01:01:32that I met with is
01:01:33looking at cognitive difficulties in
01:01:35brain tumor patients. She's completely
01:01:37recruiting all of her patients
01:01:38via the Internet. So she's
01:01:40getting her brain tumor patients
01:01:41for her intervention studies,
01:01:43you know, across the whole
01:01:44country. She's somehow gotten the
01:01:45permissions to do this.
01:01:47And so I think we
01:01:48need to be much more
01:01:49innovative, and that's what COVID
01:01:50also taught us is there
01:01:52are many more ways to
01:01:52reach people. And so we
01:01:54need to get out to
01:01:55that community of patients once
01:01:57you can tell me what
01:01:58their symptoms are. I used
01:01:59to be a lung cancer
01:02:00doctor when I was at
01:02:01the VA. That's like forty
01:02:02years ago, but, you know,
01:02:03I still have roots there.
01:02:04And so I think, you
01:02:05know, those things are possible,
01:02:07but we need to be
01:02:07able to know what people
01:02:08are suffering with and then
01:02:10interview them and talk to
01:02:11them about what they would
01:02:12like to have, what kind
01:02:13of services might be helpful
01:02:15to
01:02:16them. K. Patty, thank you
01:02:18so much.
01:02:20Thank you.