Research Initiative Comparing Proton Therapy With IMRT in Prostate Cancer

Randal Henderson, MD, MBA

The potential advantage of proton therapy over intensity-modulated radiation therapy (IMRT) in prostate cancer treatment has led to the launch of a Patient-Centered Outcomes Research Institute (PCORI)-funded initiative, which will compare the two approaches, said Randal Henderson, MD, MBA.

The research effort, which is the ongoing COMPPARE trial (NCT03561220), will look at the bowel, urinary, and sexual dysfunction Expanded Prostate Cancer Index Composite domain score between proton therapy and IMRT. Treatment duration and dosage will also be explored to determine effectiveness of shorter, higher-dose treatment compared with longer treatment at a lower dose.

"The IMRT is much more widely available; many patients can't travel to receive proton therapy," explained Henderson. "It's more expensive, and many insurance companies won't pay for protons because they need more data to justify paying that extra cost. This trial will help supply the answers that will satisfy those interested parties."

In an interview during the 2019 OncLive^® State of the Science Summit^TM on Genitourinary Cancers, Henderson, professor, Department of Radiation Oncology, and associate medical director at the University of Florida Health Proton Therapy Institute, discussed the data that led to the PCORI-funded trial, what the results could mean for the field, and interesting research on the horizon.

OncLive: What data support the use of proton therapy versus IMRT in prostate cancer?

Henderson: What we see with proton therapy is that we are able to spare the normal tissues better; that means less rectum and less bladder are treated. Rectal complications in particular are correlated with the amount of rectum that receives a dose of radiation. There are 2 types of injuries that can occur, one of which is high-dose related and [leads to] rectal bleeding and ulceration. Both proton therapy and IMRT treat a small area of the anterior rectal wall with a high dose.

However, the way the rest of the rectum is treated differs between the two treatments. Protons entirely spare the posterior part of the rectal wall, while IMRT treats the entire circumference of the rectal wall. Therefore, we would expect that there might be a difference [between proton therapy and IMRT] in long-term outcomes; in fact, the data would support that. By treating the entire circumference of the rectum with a moderate dose of radiation, we would expect to cause some degree of fibrosis and potentially affect the distensibility of those tissues. This can play out in patients experiencing rectal urgency, frequency, and even incontinence—long-term problems that can remain with them for the rest of their lives.

We did a study to actually look at that particular issue in patients who received proton therapy versus those who received IMRT. We found that the frequency with which a patient reported having a moderate or greater degree of issues associated with bowel urgency and frequency was 50% less with proton therapy than with IMRT. As such, the data would lead you to believe that there may be something to this difference that we would have predicted just from the dose symmetry.

Another interesting thing is that the radiation damages cancer cells a bit differently between approaches. IMRT primarily causes single-stranded DNA breaks, while proton therapy actually does more damage because [protons] are heavy-charged particles. Protons have a higher frequency of complex and compounded double-stranded breaks, which are harder for cancer cells to repair. Based on this knowledge, you might predict that dose for dose, proton therapy may do a better job of killing cancer cells. When we compare the control rates from our proton-treated patients, with for example, the IMRT results from Memorial Sloan Kettering Cancer Center, we find that our control rates are better than theirs in patients with intermediate- and high-risk disease,

Now, you could say, “How do you know that it's not just a different makeup of patients?” But it is intriguing, and it would fit with what we might have predicted from the radiobiology. What we need is a well-done, prospective trial to compare [proton therapy with IMRT]; that would eliminate those questions.

To this end, a PCORI-funded trial designed by our medical director has recently opened. Almost all of the proton facilities throughout the country are cooperating, as well as a large number of academic centers that don't have protons. The trial will accumulate 3000 patients in a fairly short period of time, and will allow us to really compare those results. Mayo Clinic has all three of their campuses participating in the trial as well. We are looking forward to those results and seeing if they hold up these various potential advantages of protons.

Is the lack of prospective data the reason why IMRT is still a topic of discussion?

[This trial could] show what we expect: that protons are at least as good, if not even better, in terms of control rates and toxicity than IMRT. If, when we compare this compressed trial in a randomized fashion with the standard 8-week treatment, [and find that the results] are equal, then that would address part of the cost issue [facing proton therapy]. Cost is tied to how long it takes to deliver the treatment, and the compressed treatment would be much more comparable with the IMRT cost. Insurance companies [could allow proton therapy to be] more widely available to their insured population and then expand the access to protons across the country.

Beyond the trial, what are you anticipating in terms of radiotherapy in this space?

As far as things that I would anticipate, there is going to be more interest—and there already is—in this idea of compressing radiotherapy. We are looking at 4 weeks versus the traditional 8 weeks, but even shorter schedules are being extensively studied. With proton therapy, we would also be able to do the shorter schedules and spare the normal tissues even better than IMRT could. That is a direction we are looking at.

We are also excited about something called SpaceOAR Hydrogel, which helps protect the rectum from high-dose injury that can occur with protons or IMRT; this is becoming more widely available. What we see with the SpaceOAR placement is, instead of having the rectum right behind [the prostate] and having the anterior rectal wall being the high-dose area, you can put a needle—under ultrasound guidance—between the anterior rectal wall and the prostate. You can open that up with some saline and put a hydrogel, under ultrasound guidance, into that space. That will hold that anterior rectal wall about 1 cm away from the prostate for 3 months; then it dissolves, and it's gone.

During that time, you can use protons or IMRT and get that anterior rectal wall out of the field. That has almost eliminated the problem that we have seen with rectal bleeding and ulceration. However, [SpaceOAR] is a newer procedure that is not as widely available. It's is an exciting way to help improve the results we’re seeing, even with existing technology that is available across the country.