Exploration Into Stereotactic Body Radiation Therapy for Pancreatic Cancer

In an interview withTargeted Oncology, Herman, co-director, Pancreatic Cancer Multidisciplinary Clinic, associate professor of Radiation Oncology and Molecular Radiation Sciences, John's Hopkins Medicine, explained how the use of stereotactic body radiation therapy has evolved and how the therapy could better target tumors without extending its toxicities to different parts of the body.

TARGETED ONCOLOGY:

How might stereotactic body radiation therapy work in pancreatic cancer?

HERMAN:

Stereotactic radiation therapy has been around for a number of years, but it was primarily used for CNS tumors. Over the past several years there have been improvements in terms of the technologies that we have available to us that allow us to now give very focused, pinpoint radiation therapy to different tumors throughout the body.

Some of those improvements have been to control breathing motion, because we've found that tumors such as pancreatic or liver tumors can move quite a bit during breathing. So we have to be able to either track that breathing motion or we have to control it by managing that patient's breathing, so for example to have them inhale deeply and hold their breath for a period of time, freeze the tumor in space and then treat it.

We can also put little gold markers, or what is called fiducials into the tumors, which allows us to image them while we treat them and turn on the beam when it's in a certain location. So those are two very important improvements in terms of how we deliver radiation therapy for the body, which has allowed us to coin it stereotactic body radiation therapy as opposed to just stereotactic radiation therapy.

TARGETED ONCOLOGY:

How does stereotactic body radiation therapy play into the neoadjuvant setting for pancreatic cancer?

HERMAN:

Historically, patients who are trying to get surgery will receive a combination of chemotherapy followed by chemoradiation, or chemoradiation alone. The goal of giving these therapies is to try and improve the likelihood of undergoing a margin negative resection. That's important because we've learned from several studies that having a margin positive resection will generally result in poor survival.

In addition, we are now developing new systemic therapies and more effective systemic therapies for pancreatic cancer, such as FOLFIRINOX and Abraxane plus gemcitabine. With these therapies, patients are able to have a longer progression-free interval, but they get to a point where they can't tolerate a lot more chemotherapy. Adding in radiation therapy at that point can be very effective at helping control local progression of the tumor, which can lead to pain, discomfort, and sometimes bowel obstruction, which could inhibit the patient's ability to eat and do well.

TARGETED ONCOLOGY:

What is the safety profile for this therapy?

HERMAN:

It's emerging, and I think that we are learning a lot as we go along. Albert Koong and Daniel Chang and others did the very early work at Stanford, and they were the ones that really helped get it off the ground. They started off using a really high dose to the tumor. It was quite effective with about a 90% local control rate, but unfortunately, it was a little difficult for the bowel, which is just adjacent to the duodenum, which is just adjacent to the tumor, to tolerate that dose. A number of patients did develop ulcers or gastrointestinal bleeding that can be, in some circumstances, fatal.

Over the last 10 years or so, we have worked very hard to try to improve upon the safety profile or stereotactic radiation for pancreatic cancer. We've done that by controlling the breathing motion, using fiducials, and having very strict dose constraints. In other words, we are very mindful of the dose that the bowel and the stomach are getting during the radiation therapy. If we can't achieve a safe dose to those organs, we will back off on the dose that we deliver to the actual tumor in order to maintain that safety profile.

Now, most institutions will give it over a 3- to 5-day period, will use motion management, image guidance, and these improvements and the way it's delivered appear to really decrease the risk of any long-term toxicity, which is usually 3 months after the radiation, to about 5% or 10%, which is much more favorable than what was reported previously.

TARGETED ONCOLOGY:

How do you determine which patients would be appropriate to receive stereotactic body radiation?

HERMAN:

I would always stress that the first and most important thing is that patients should be evaluated in a multidisciplinary setting where there is a tumor board or an actual clinic, where surgeons, medical oncologists, radiation oncologists, and other specialists review each case and especially if a patient has a proper performance status to undergo neoadjuvant therapy, for example. Can the patient tolerate chemotherapy? What are the goals of the patient themselves? In that setting we also review a pancreatic cancer protocol for each patient and make sure that we accurately stage the patient.

We want to make sure that they don't have metastatic disease because then in that case we would focus mainly on systemic therapy, and then we want to separate patients into either borderline or locally advanced. In that situation, if it's borderline resectable then we are very hopeful that we're going to get them to surgery. We'll give about 4 to 6 months of chemotherapy, 5 days of stereotactic radiation, and then try to get them to surgery. In those circumstances, if we are treating a little more bowel, in some cases it may be appropriate if we're very confident that they're going to surgery then that bowel is going to come out during surgery.

On the other hand if you have a patient with unresectable disease who really has a really low likelihood of going to surgery, we have to be even more careful because those patients may never go to surgery. If we're not mindful or careful, we can cause serious toxicities such as ulcers. So we not have a good grasp on what some of the dose constraints are moving forward.

The one thing that's clear is that if the tumor is invading into the duodenum, or invading into the bowel, and those patients are not likely to go to surgery, we do not treat those patients with stereotactic radiation therapy because the risk based on our previous experience is really pretty high. In those cases, we would use standard radiation given over a 5- to 6-week period to try to allow the bowel to recover from the radiation and therefor decrease the likelihood of toxicities.

TARGETED ONCOLOGY:

What would you say is next for stereotactic radiation?

HERMAN:

The real key is that we need to test it in a prospective randomized study. There is a randomized clinical trial called the Alliance Trial moving forward that will compare FOLFIRINOX alone versus FOLFIRNOX plus a short course of stereotactic body radiation therapy, or what we call high-dose image guided therapy. So it's like stereotactic radiation but it's a little bit of a larger volume and it's a way for us to deliver radiation without all the technology, because some places don't have all the technology you'd need. This will allow places to still enroll in the trial, but we are really hopeful that most patients will be treated with stereotactic radiation therapy.

That trial should be opening in the spring, and we're hoping since it's a cooperative trial, we'll be able to answer the question of what the true benefit is of stereotactic radiation in that setting.

The other exciting thing moving ahead is that we have trial for locally advanced pancreatic cancer patients, where we're integrating stereotactic radiation therapy with immunotherapy. That's exciting for us because immunotherapy can offer a treatment that has non-overlapping toxicities with chemotherapy. That's one of the biggest things — we have patients that do really well for a while, but they can no longer handle aggressive, systemic therapy, so having other therapies that we can integrate is really helpful. We're hopeful that immunotherapy with radiation might further enhance the effect of immunotherapy.

The other thing is patient selection is really key. In the Alliance Trial, as well as the RTOG 1201 study, we're hoping to integrate biopsies of the tumors prior to treatment. With these biopsies, we're going to do next-generation sequencing and we're going to get liquid biopsies to look at circulating tumors DNA to try to get a sense of the tumor burden.

In theory, we hope that in the future there will be a certain profile of patients that we would decide not to take to surgery because we know that the risk of progression is so high and we might monitor those patients. On the other hand, if patients have a very favorable profile, those are the patients we would put through a Whipple.