Nov 12, 2020
Dr. Daniel T. Chang, a radiation oncologist and specialist in gastrointestinal cancers (GI) at the Stanford Cancer Institute discusses clinical trials that are potential game changers in the treatment of GI cancers. Dr. Chang also highlights the expanding use of SBRT to improve outcomes for patients and its growing impact in a new era of radiation oncology.
Transcript
ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Geraldine Carroll, a reporter for the ASCO Daily News. I'm delighted to welcome Dr. Daniel Chang to the podcast today.
Dr. Chang is a radiation oncologist at the Stanford Cancer Institute and professor at Stanford University. His clinical focus is on gastrointestinal cancers, and he joins me to discuss several clinical trials which are potential game changers in the treatment of GI cancers. And we'll discuss the promise of therapies, including SBRT, to reduce toxicity and improve outcomes for patients.
Dr. Chang reports no conflicts of interest relating to the issues
discussed in this episode. Full disclosures relating to all Daily
News podcasts are available on our transcripts at
asco.org/podcasts. Dr. Chang, welcome to the ASCO Daily
News podcast.
Dr. Daniel T. Chang: Thank you. It's a pleasure to
be here
ASCO Daily News: Dr. Chang let's start
with the PROSPECT trial, which has garnered a lot of attention from
both radiation and medical oncologists (NCT01515787).
This is an active trial in the rectal cancer setting that has phase
II and III components. So this study involves chemotherapy alone or
chemotherapy plus radiation in the treatment of patients with
locally advanced rectal cancer. So what are your thoughts about
this study? Would chemotherapy alone be a game changer in this
setting?
Dr. Daniel T. Chang: Well, it would certainly
upend or change the standard of care which has been in place for
over two decades. Preoperative radiotherapy has really been around
for really a much longer period of time. But in its current form,
the standard of care was set by the German Rectal Trial, which was
preoperative chemoradiation followed by surgery and then
chemotherapy (DOI: 10.1056/NEJMoa040694).
There are larger changes in that overall paradigm, but the key
feature of the PROSPECT trial is the omission of radiotherapy and
using chemotherapy alone. That certainly will be a game changer,
and the rationale behind it is mainly to avoid some of the
long-term morbidity and toxicity of radiation for these patients.
And so for these patients, if they can get chemotherapy alone and
avoid the use of radiation, that certainly would hopefully be a
benefit for them, but it could be obviously a big change in how we
manage rectal cancer moving forward.
Probably the one point to add about the PROSPECT trial is that the
patients that were enrolled were considered intermediate risks. So
they didn't represent patients with really advanced disease. These
are patients with kind of early T3 tumors. They had limited nodal
disease, so they couldn't have more than N1 disease. And they had
to be eligible for organ preservation.
And so if the results do show that chemotherapy may have
equivalents to chemoradiation, it still doesn't mean that there
isn't a role for radiotherapy. It just may mean that for those that
are at lower risk of recurrence--of pelvic recurrences,
specifically--chemotherapy could be an adequate substitute. But
radiotherapy for more advanced disease--patients with T4 tumors or
with more bulky nodal disease--there will likely continue to be a
goal for radiotherapy in that setting.
ASCO Daily News: Right. And we'll be
waiting on results of this trial in about a year. Well, let's focus
on nonoperative approaches to manage rectal cancer. The OPRA trial
yielded promising preliminary results earlier this year. And this
trial looked at the safety and efficacy of organ preservation with
a watch and wait strategy and total neoadjuvant therapy (DOI:
10.1200/JCO.2020.38.15_suppl.4008).
This nonoperative approach has been around for a long time, but
oncologists in the United States have been hesitant about it. Why
is that? And do you think the OPRA study will change their
minds?
Dr. Daniel T. Chang: The OPRA trial really touches
on this nonoperative management, which was really pioneered by a
group in Brazil. And it has really spread slowly but surely across
to other parts of the world. But surprisingly or not surprisingly,
it hasn't really had a huge uptick in adoption here in the United
States.
And I think the biggest reason is just because it's such a big
departure from the long-standing standard of care, which of course,
involves surgical resection. And I think many--for good reason,
many people are hesitant about omitting such a important part. I
mean, it's always thought that surgery is the curative option, or
the curative modality that is required in order to properly
maximize the chance of cure for these patients.
But as more and more data accumulates--and it's been accumulating
through multiple retrospective studies, single arm prospective
studies, and a very large international database, the results have
been surprisingly consistent, that in a very carefully unselected
patient population where there is a complete clinical response,
through very rigorous surveillance and follow up, these patients
could potentially be managed without surgery, provided that you can
detect and catch a recurrence soon enough to be able to offer
salvage therapy.
The OPRA trial is significant because it's the first prospective
trial in the United States that has really adopted nonoperative
management. And MSK, Memorial Sloan Kettering, the group that led
this trial, I mean, they've been kind of pioneers in the United
States for using this approach. So hats off to them for really
conducting this trial.
The trial wasn't specifically--the experimental design isn't
explicitly to test nonoperative management. It's mainly to test a
different sequence of chemotherapy followed by radiation,
chemoradiation then surgery versus chemoradiation, and then
chemotherapy and then surgery. But they did allow for nonoperative
management or observation for these patients.
And what the interesting finding, of course, that they reported at
ASCO earlier this year was that for patients who started with
chemoradiation, they actually had a higher rate of organ
preservation at 59% versus 43% if you started with chemotherapy. So
a few interesting findings I think from this trial are, one, that
nonoperative management seems like it certainly is feasible, at
least demonstrated in this prospective setting.
And then it definitely gives some insight as far as what is the
optimal preoperative, or the optimal sequence to give for patients
and try to get them to a nonoperative management approach. So I do
think that this will hopefully be, similarly, a game changer in the
sense that it will, one, kind of break the barrier and allow for
hopefully more of these prospective trials to be done.
And really to kind of let people know it's actually OK to start
thinking about using nonoperative management, which I suspect is
still--is actually being used more frequently than what we suspect
just because for patients, there is a huge incentive for them to be
managed nonoperatively because they don't want to have a permanent
colostomy. So many of them, they vote with their feet. They come in
with a strong bias about it.
And so for those that are more open to the idea, and they have seen
the literature, and they've seen the studies, and they feel more
confident about it, we've been doing that here at Stanford off
study for patients who are very, very passionate about avoiding
that surgery. And so based on that data, we've been offering it. So
I do think that the OPRA hopefully will be ushering this new era of
nonoperative management in trials and also mean in practice.
ASCO Daily News: Right. Well, I'd like to
ask you about some of the work that you and your colleagues are
doing at Stanford. So staying on the theme of organ preservation,
you are currently accruing for an organ preservation trial. What
can you tell us about it?
Dr. Daniel T. Chang: Yeah. So we're really excited
about this trial. We actually have been talking about it for many,
many years, and fortunately, we've been able to finally open that
with one of my junior colleagues. Her name is Erqi Pollom, MD. And
it's a really novel design, which I think really kind of doubles
down or goes all in on the nonoperative approach because if your
true goal is to really get patients to a nonoperative management,
you want to basically maximize the number of patients who achieve a
complete clinical response (NCT04380337).
And to do so, you would then want to basically offer maximum
therapy. Most of the nonoperative approaches usually involve a kind
of standard radiation with 5-FU chemotherapy, which works well, and
it does its job, but it has kind of a--in my mind, it has sort of a
ceiling as far as how effective we can get patients to a complete
clinical response.
And so if we really want to move the needle on that, then we
probably have to alter some of the treatments that we give. So for
instance, we really intensify the chemotherapy that these patients
get. So instead of just FOLFOX or XELOX chemotherapy, we actually
give FOLFOXIRI. So that's going to be the most aggressive kind of
combination of chemotherapy that we can give that will address
systemic therapy, but it will also maximize the response to the
tumor.
And then we also give short-course radiation, which we think
has--more and more data has been showing that short-course actually
is very equivalent to long-course chemoradiation. And so we give
short-course 5 gray times 5 with actually an extra boost of 30 gray
and 6 fractions. So with kind of that extra radiation dose plus the
combination of FOLFOXIRI, we actually think that this will
hopefully maximize the chance for patients to basically have an
organ preservation approach for them.
And so we recently opened that trial early this year. The trial has
been accruing quite well. When patients hear that there's an organ
preservation option for them, it's usually not very difficult to
get them to be interested in the study, provided that, again,
they're willing to undergo the very rigorous follow up schedule
that we have that involves imaging and very regular, like every
three month endoscopies to assess for response.
ASCO Daily News: Right. And what is the
name of that study?
Dr. Daniel T. Chang: The study is actually called
SHORT-FOX. So SHORT, of course to signify the short-course
radiotherapy option. And FOX just because every chemo regimen has a
FOX in it.
ASCO Daily News: All right. Well, can we
talk about the emergence of perioperative chemoradiation for GI
cancers? The TOPGEAR phase III randomized trial out of Australia,
the vast majority of patients in this study did not experience an
increase in treatment toxicity or surgical morbidity (DOI:
10.1245/s10434-017-5830-6).
Do you think this study will change standard of care?
Dr. Daniel T. Chang: I do, actually. So one of the
raging questions that is I think going to continue to rage and
probably get bigger is really the whole question of CROSS
preoperative chemoradiation, which has been kind of long
established for several years now based on the CROSS trial, versus
perioperative chemotherapy, which now the chemotherapy regimen is
FLOT-4 (DOI: 10.1016/S1470-2045(15)00040-6).
And there hasn't been a published head-to-head trial looking at
those two approaches. And so TOPGEAR is a way to sort of blend the
two together, where they give perioperative chemo, but in one
arm--in the preoperative setting, they actually substitute in
preoperative chemoradiation. So it's really showing, does the
addition of preoperative chemoradiation to perioperative
chemotherapy improve outcome? And so clearly, the results of this
trial will be very, very relevant to those who manage gastric and
gastroesophageal cancers.
For gastric cancers, for pure stomach cancers, radiotherapy plays a
pretty minimal role now, just based on many of the trials that have
come out, whereas for gastroesophageal cancer--so cancers more of
the GE junction of the distal esophagus--radiotherapy plays a
larger role based on the CROSS study. But the issue is really I
think most people will think of lower esophageal adenocarcinomas
and upper or gastric adenocarcinomas in general as probably
biologically similar.
So it seems a little--it's always been kind of puzzling to me that
we have sort of these--a very strict kind of different approach
simply just by the position or location of a tumor that likely is
biologically similar. So what's nice about the TOPGEAR, and other
trials that are coming down the pike, is that they basically kind
of blend the two together.
And so whatever treatment approach emerges from this, you probably
could extrapolate or apply really to both gastroesophageal
adenocarcinomas as well as gastric cancers. So I think this trial's
actually really exciting, and we're really interested in seeing the
results as they come out.
ASCO Daily News: Dr. Chang, you
specialize in Stereotactic Body Radiation Therapy, or SBRT, for
abdominal tumors. This is such an exciting area of radiation
oncology. Do you anticipate that more and more data in the future
will show clear evidence that SBRT can help improve overall
survival?
Dr. Daniel T. Chang: Absolutely. So this is
definitely one of the, if not the most exciting area in radiation
oncology because of the role SBRT can play. For probably the last
15, 20 years or so, a lot of the focus has really just been on
perfecting the technique of SBRT, and really finding the
indications for it.
And I think we've clearly are--have moved into or are moving into a
new area, where we're really expanding the use of SBRT for
situations now, mainly in the setting of oligometastatic disease,
patients with limited metastatic tumor burden. And as you--in your
question, you're asking, do you anticipate more data to come in the
future? We actually are starting to get a lot of really good data
coming out in the randomized prospective setting of using either
aggressive radiation therapy or SBRT in improving survival in
patients who have limited metastatic disease.
We've seen that now in patients with lung cancer, with prostate
cancer, with head and neck cancers. And it seems like there's a
pretty active pipeline of trials that will be coming out I think
over the next several years that will hopefully continue to show
this improvement.
And I think it's a really great frontier, basically, because for
the longest time, the model has been chemotherapy for patients who
have metastatic disease. And we all know that patients with
metastatic disease are a heterogeneous group, where some will have
obviously very poor prognosis, and for them, aggressive systemic
therapy would be the more preferred approach.
But for those, I think as we're getting more effective
chemotherapy, we're seeing better outcomes. We're seeing more
indolent natural histories because of the effectiveness of
chemotherapy. Radiotherapy, especially SBRT, can play a big role in
these patients by basically wiping out any remaining residual
tumors.
And the end goal is hopefully to get improved survival, but
oftentimes, in my practice, too, sometimes the end goal is to give
patients a break from chemotherapy. Many of them have been on
chemotherapy for months and even years. And it's done a great job
for them because they've been in this holding pattern of very
minimal or very slowly progressive disease.
And sometimes either they're having a lot of toxicity, or their
quality of life just isn't where we want it to be, switching to a
local therapy like SBRT, which has relatively low side effects and
acute toxicities, this can actually be quite impactful for these
patients.
So I very much anticipate, especially as there's more and more
interest, more and more trials being developed, that SBRT will play
an expanded role in patients with not just oligometastatic disease,
but there is a whole frontier of patients who have oligoprogressive
disease, meaning they have progression in limited sites, whereas
other tumors may be relatively controlled or stable.
And some folks have even talked about using SBRT in the
polymetastatic setting, meaning patients who have more than
oligometastatic disease. Radiation--I think it's incumbent on us as
a field to be able to find a way to deliver radiotherapy in a safe
and feasible way. But that is definitely something that is on the
horizon, and is probably going to be a question that we will
continue to kind of be asking ourselves as a specialty in the
coming years and decade.
ASCO Daily News: Absolutely. Well, Dr.
Chang, is there anything you'd like to add to our discussion today
before we wrap up the podcast?
Dr. Daniel T. Chang: I'd probably just add that I
think the future is really, really bright, just for oncology
because of just the amazing developments that are being I think
made on a regular basis. Obviously, immune therapy has been a game
changer, all the targeted agents that come out.
Where I've been excited particularly for radiation oncology is that
with all of these new advances--I mean, many of the questions that
we used to ask back in the time where--does radiotherapy have a
role in the setting where there was really limited systemic therapy
options? Where prognoses may not have been as good, radiation may
not have been as helpful.
But I think in an era where we're starting to really see some great
outcomes with systemic treatments, it's really a great time to be
re-ask some of these--sometimes even some very basic questions that
we thought we answered 20, 30 years ago. But now with a completely
different context, different era, we should really think about
maybe re-asking those questions again. And so I think it's just a
really great time and a great opportunity, and a lot of exciting
things to look forward to.
ASCO Daily News: Well, thank you very
much, Dr. Chang, for sharing your valuable insight with us today on
the ASCO Daily News podcast.
Dr. Daniel T. Chang: My pleasure. Thank you for
having me.
ASCO Daily News: And thank you to our
listeners for joining us today. We'd love to hear from you. So
please take a moment to rate and review us wherever you get your
podcasts
Disclosures: Dr. Daniel T. Chang
Stock and Other Ownership Interests: ViewRay
Research Funding: Varian Medical Systems
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