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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.


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 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

Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.