Applying what we’ve learned from clinical trials about cachexia to cancer survivors

Applying what we’ve learned from clinical trials about cachexia to cancer survivors


>>Thank you. Iím Jeff Crawford. Iím a medical oncologist at the other University
in North Carolina -Duke. I want to thank the organizers for inviting
me. Iíve been involved in clinical trials for
a number of years and fortunately was recently involved in some
cachexia studies, and here are some disclosures. I canít
start without thinking about Ken Fearon, who died about a year ago. Seems sometimes like days ago,
sometimes like a year ago. He was a major contributor to our field and
would love to be here today and weíd love to have him here for his insightful
comments. But you’ll be hearing an effort from him as
we go along.>>So I thought Iíd start with a case. This is a 72 year old woman in my practice
who presented with a cough and back pain, poor appetite, unintentional
10 pound weight loss. She was fatigued and had to
close her law practice. She had a minimal smoking history, no other
comorbid disease and you can see her vital statistics there. The long and short of this is she was evaluated
for a Stage IV adenocarcinoma of the lung and her treatment options were
largely limited at that point to platinum-based chemotherapy and her oncologist was starting
that and decided to refer her to a palliative care
specialist, largely because of the work of Jennifer Temel a few years ago which was published
in the New England Journal of Medicine that shows that
integration of palliative care, as probably most of you
know, at the same time as management of a patientís advanced cancer (particularly lung
cancer) not only improves quality of life but also survival. This is now being helpfully replicated in
an Alliance trial thatís being done in a multicenter fashion.>>So at this point we are left with management
of pain, cough and fatigue. But what about her anorexia
and weight loss? What should we do in clinical practice now? Do we get a nutrition consult, do we
recommend an exercise program, is there some intervention like megestrol acetate or some
combination of the above? And when you look at our experts in the area,
as seen at NCCN, you can see a long litany of potential interventions,
but you can see most of these are evaluating weight loss, trying
to reverse the reversible causes of anorexia, and doing a medication, looking for endocrine
abnormalities, and considering an exercise program, considering a nutrition consult. Those in the field I
think would like a stronger recommendation than consideration here. And then reevaluating. So there’s
no therapeutic intervention currently recommended. So clearly our field is really suffering for
better direction, better studies, better guidance
and more consensus.>>So this is a definition that Ken and colleagues
developed, and Vickie has alluded to this already, to come
together about a consensus definition in the field of cancer cachexia, which I think still
holds well today. Cachexia is a multifactorial syndrome defined
by an ongoing loss of skeletal muscle mass that can’t be
fully reversed by conventional nutritional support and leads to progressive functional
impairment. We
know, from work from Vicki and others, that muscle wasting in lung cancer patients is
very prevalent and you can see itís present. If you look at just low BMI, a BMI of less
than 18.5, that happens in a minority of patients. But if you look at muscle wasting, itís almost
half of our patients with diagnosis present with muscle wasting and that rises
to about two thirds by the time they are through the course
of their illness.>>An important paper that hasn’t been mentioned
today (so I’m glad I got a chance to do this) is Lisa
Martin’s work takes some roughly simple measures looking at BMI and looking at weight loss
and combining those two and looking at the impact
that has on potential outcomes. This is in more than
8000 patients with cancer in Canada and Europe, and looking at those variables and outcomes
and following them for survival. One can see here a diagram that shows on the
x-axis: the survival by BMI in months, and 13 months for high BMI patients
and four months for patients with low BMI. And the other
axis, on the y-axis, patients with no weight loss 17.3 months down to 4.4 months -you can
look at that and put a grid together and grade this from
grade 0 in the white boxes down to grade 4 in the yellow
boxes and look at outcome and divide it by performance status. Youíll see a pretty dramatic effect. Youíll see that good performance status patients
have a 27.8 months survival for that group of patients
with high BMI and no weight loss. On the other end, the patient with severe
weight loss and low BMI has six months, and that’s worse than the
poor performance test. So these are easy measures and ones
we should incorporate our practice that don’t require body composition but would at least
give us a direction on who needs further evaluation.>>The end result of this disease process
and muscle mass as both clinical effects and metabolic effects
ultimately leading to a decline in independence, increased hospitalization and decreased responsiveness
to chemotherapy and increased mortality. So there are a lot of complex interactions,
and we touched on this a little bit, but this is a balance
between muscle loss and muscle growth and what I want to do is
focus on two agents that have been in the clinic recently. One is a selected antigen receptor modulator
which has an impact on blocking muscle loss. And the other is ghrelin on the other end
that can stimulate muscle growth. And we will see different trial designs and
different results but I think thereís some promise with both agents with more lessons
for the future.>>So first enobosarm, an androgen receptor
modulator, these are agents that have been developed to
preserve the beneficial effects of androgen while removing those of higher risk. This particular molecule
has been designed so virilization, prostate hyperplasia and lipid effects have been dialed
out while maintaining effect on muscle and bone. In the Phase 2 trials, it looks like a promising
agent we can see on the left: lean body mass for Phase II to
be a cancer cachexia trial. Thereís another study in elderly
men and postmenopausal women. In a sarcopenia trial, all three of which
show the oral agents compared to placebo a significant impact on
lean body mass. At the same time physical function is
measured by stair climb power in the first two trials and by a bilateral leg press in
the third study. And
again showing what appear to be significant differences. This led to the development of two
randomized phase 3 trials that we were involved with, one of them was done in patients with
advanced lung cancer getting platinum and a taxane
regiment, the second was platinum and a non-taxane regiment. These are patients with newly diagnosed advance
stage lung cancer, good performance status, no criteria for weight loss included
per se and you can see the endpoints the day before. Our
primary endpoints were a lean body mass (by DXA) and physical function by stair climb
power that was also looked at on day 147 in the two studies.>>So we look at the lean body mass responder
analysis and what one can see is that surprisingly in the
control population getting chemotherapy alone, about a third of patients maintained their
lean body mass or increased it. Whereas there was a difference statistically
in favor of the enobosarm-treated patients, but I think it was blunted by the
effects chemotherapy had in the positive patient population. Interestingly when you look at the whole population
you could see a difference, however, in the enobosarm group that had an increase of about
2 kg in lean body mass in the first study, and about a
one to one and a half in the second trial compared to the control population that had
a decline. So
there was clearly an effect on lean body mass by these two studies with these enobosarm.>>Looking at the continuous variable analysis,
the endpoints if you looked at stair climb power between
the placebo and enobosarm group, there was a statistical difference in the first group
with the taxane and highly statistically significant difference
in lean body mass. That was also seen in the POWER trial as
well, where there was statistically significant difference here, but stair climb power failed
to be validated in the second study. Unfortunately the study didn’t meet uniform
endpoints, didn’t meet the regulatory criteria that the FDA had and the CMA had. They’re looking for both a functional change
as well as a lean body mass. I will say this, and a lot has been said about
this study. One looks just at lean body mass
responders, whether they were on chemotherapy alone or on chemotherapy plus enobosarm, there
is a relationship. You can see the lean body mass responders
doesn’t maintain lean body mass, and there is
improvement over the stair climb power compared to the non-responders. So the relationship exists
but perhaps not strong enough to meet the endpoint.>>Let’s talk about the Ghrelin story. Ghrelin is an agent released by the stomach
and is the ligand for the ghrelin receptor that produces the release
of growth hormone. And it simulates a number of different
pathways to help regulate body weight, lean body mass, appetite and metabolism. Anamorelin is an
orally active, ghrelin mimetic/receptor agonist, and in the phase 2 trial it also showed significant
effects on increasing lean body weight at 12 weeks
in lung cancer. So the trials chosen for the development of
this agent were also in lung cancer, but they weren’t at initial diagnosis – the patients
already had established cachexia and had already lost
5% of body weight or more. And they could be at diagnosis or
any point in their time course. And the patients were randomized to Anamorelin
versus placebo. Again
looking at lean body mass, you can see that in both trials a significant improvement was
seen in lean body mass of both studies. Interestingly though, they picked handgrip
strength as their endpoint and unfortunately it showed no impact of a decline
in handgrip strength in both and we can talk about it
whether it was the best measure and what some of the limitations might be but unfortunately
their functional endpoint was not successful.>>What was successful was an improvement
in weight. We can see a nice improvement in body weight
in the anamorelin group compared to placebo in
both studies really so that was significantly different. This
is about a 3 kg increase over a 12 week period. And also by the anorexic-cachexia patient
reported outcomes scale that was significantly different
again in both trials. We look at fatigue: it appears there
was a significant difference in the fatigue scale in the first trial, wasnít seen in
the second study. And
again speaking to these difficulties of fatigue and its multimodal factors involved with it. So I was
discussing, when this data was first presented and I asked a group of colleagues about what
they would do in this situation. If they had these trials and had these results
and had this drug available that improved appetite and improved body weight
and improved lean body mass with minimal toxicity, would they prescribe it in their practice
and the answer was pretty uniformly yes. Unfortunately when
the regulatory agencies looked at this as in the US and Europe, in the absence of functional
improvement they felt that the data was not sufficient in and of itself for approval.>>So I think we’re back to the drawing board
a little bit. I think there’s promising agents that we just
havenít used in quite the right way. Maybe we havenít developed our clinical trials
quite perfectly and Iím interested in comments you may have. One of my residents and I are looking back
at the data, and this is some from our trial with the power
studies looking at the enobosarm patients. But this is the
control population (just the placebo group) and we want to understand if we could what
the patient factors were discussed it with muscle loss
and what the factors associated are with muscle function
change. Clearly these are patients starting treatment
who have undergone weight loss before but look
at weight loss during treatment there is a relationship between weight change and lean
body mass and we saw overtime some gaining some losing. If you look at lean body mass as an endpoint
and try to look at baseline characteristics there’re trends
in some of the data but the only thing that fell out was a
patient with more advanced disease had more significant change in lean body mass then
did the patients with less advanced disease. But the other factors were not as statistically
significant.>>When we looked at the stair climb power,
interestingly the taxane population had more of an impact
and had more effect on muscle by function. People who quit smoking had a bigger effect. Actually this is
a negative effect: so the patients the quit smoking morning more than a year ago had less
of an improvement in stair climb power and some
other endpoints as well. So this is a work in progress to try
to understand: is there a subset of patients will be more benefited by these interventions
than others at the time of diagnosis? The other thing weíve learned, and I think
we heard this today, change in stair climb power and change in lean body mass are
not necessarily correlated, particularly over a short time
interval like this, of a matter of months. So it brings us back to cancer and concepts
of precachexia, cachexia and refractory cachexia. Whatís the right time point to intervene? In the work of Anna
Morlan, they approach the patients more at cachexia or in the refractory cachexia stage,
and our studies were done more in this window. Neither were totally successful, although
both showed some impact of these agents that could’ve been predicted
from preclinical data. And I think, to me, it’s still trying to
correlate with the patient: what the best functional outcomes are, how do we show the
effect and benefit of the agents, and whatís the best
population. And this is an algorithm also from that paper.>>In summary, Iíd say that cancer cachexia
is prevalent at diagnosis and increases in frequency and
severity during the disease and treatment course of our patients (in lung cancer but
also in other advanced cancers). Muscle wasting in sarcopenia is central to
cancer cachexia, both in the molecular and clinical level and impacts function, quality
of life, treatment response and toxicity and survival. Nonpharmacologic approaches really remain
our mainstay, with nutritional counseling and physical
training exercise should be recommended for all our patients early in their disease course. And maybe
selective pharmacologic interventions we have that mainly reduce the depression pain and
other factors that may be interfering. And I think there’s promising approaches for
early detection and monitoring as well as new agents for treating this disease
that hopefully will come forth in the years ahead. And Iíll
stop there. Thank you.

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