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Join a clinical trial: Using PET/MRI in HIFU Planning

Dr. Timothy J. Daskivich is a urologic oncologist in the Cedars-Sinai Urology Academic Program and the director of Health Services Research for the Cedars-Sinai Department of Surgery.

Prostatepedia spoke with him about his clinical trial on using high-resolution PET/MRI in planning high-intensity focused ultrasound (HIFU) for prostate cancer.

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Why did you become a doctor? What was it about medicine that drew you in?

Dr. Daskivich: I always knew that I loved science, but I wanted to do something where I could impact individual lives. I’m also a people person, and I love to get to know people and hear their stories. Being a doctor is a kind of mash-up of those two interests: my love of science and discovery with the human aspect of being a doctor.

Now I’m a physician-scientist: I do the science part of my work half of my time, and for the other half, I see patients and operate. They’re related but very different, and I love the dichotomy.

I’m sure one informs the other.

Dr. Daskivich: Absolutely. I actually have a good example of how my research connects these two parts of my job. I have a Mentored Clinical Scientist Research Career Development K08 Award from National Cancer Institute that aims to improve communication between doctors and patients about life expectancy after a new diagnosis of prostate, kidney, or bladder cancer. This study involves recording treatment consultation consultations between doctors and patients to better understand what is being said about life expectancy in these discussions. We follow this with a structured interview with the patient to ask about what worked well or what could have been improved. Based on what we observe, we’re planning to create a patient-centered approach to discussing life expectancy. This study allows me to talk to the patients, hear their stories, and then bring their perspective back to physicians to try to improve communication. It’s a lot of fun, and one aspect informs the other.

Can you talk to us a bit about the context of the clinical trial you’re running?

Dr. Daskivich: Our clinical trial involves testing whether fluciclovine PET-MRI can improve localization of tumors within the prostate (compared to standard multiparametric MRI) prior to focal treatment with high-intensity focused ultrasound (HIFU).

To help you understand why this trial is important, let me first give you some background. For many years, we used surgery or radiation to treat the entire prostate for patients with prostate cancer. We either removed or radiated the entire gland. That was the standard of care for a long time. But the problem with whole-gland treatment is that it incurs a lot of side effects—erectile dysfunction, urinary incontinence, or irritative urinary symptoms—by damaging structures near the prostate like the nerves that supply the erectile function of the penis and the bladder neck.

In order to minimize those side effects, there’s been a movement to consider focally treating the prostate cancer lesions and leaving the rest of the prostate intact. That had been a pipe dream for a long time, until recently when the technology has become available to identify and focally treat prostate cancer lesions in a minimally invasive and highly precise way. It’s actually a confluence of three technologies that have made focal therapy possible.

The first of these technologies is high-intensity focused ultrasound (HIFU). HIFU directs high-intensity ultrasound waves to a point in space, and that point is destroyed. It’s a little bit like using a magnifying glass to harness the rays of the sun to burn a leaf. When you pass your hand between the magnifying glass and the leaf, you don’t get burned. With HIFU, you can place a probe into the rectum, direct the ultrasound waves to destroy an area in the prostate and destroy it while leaving all the intervening tissue unharmed.

The second technology is MRI, which we use to localize cancers within the prostate. MRI has about 80% sensitivity for detection of high-grade cancers within the prostate. And not only can it detect them, but it can define exactly where they are.

The third technology is MRI-ultrasound fusion. This technology allows us to overlay MRI images—including the location of tumors—onto ultrasound images in real time. This is important since we use ultrasound as our primary imaging modality to direct HIFU to the areas of the prostate that are affected by cancer. Now with MR/US-fusion technology, we can superimpose the location of tumors as identified by MRI directly onto the ultrasound when we’re targeting our HIFU beam.

All of these technologies—MRI of the prostate to identify location of tumors, ultrasound fusion to target the tumors in real time, and HIFU to precisely transmit energy to these areas—have made focal therapy of the prostate possible.

Our study acknowledges the fact that focal treatment of prostate cancer is entirely dependent on imaging. If I’m going to take out the entire prostate gland, there is a huge safety net for error. If we thought that the cancer was on the right side, but lo and behold, there were a few lesions on the left, it’s no problem–we’ve taken the whole thing out, so we’ve removed the unseen cancer. However, now that we’re doing focal therapy, that safety net is gone. If you fail to detect a prostate cancer prior to doing a focal treatment and therefore don’t treat that area, then you haven’t fully treated the cancer.

In this study, we’re using high-resolution PET/MRI to precisely identify prostate cancers during HIFU planning. Before HIFU, all the patients on the trial get a high-resolution MRI (six-fold improved resolution compared with standard MRI) and fluciclovine PET-MRI to map out where prostate cancers may be located. We then biopsy all lesions that are positive on the PET or on the high-resolution MRI using ultrasound fusion technology. Then based on that map, we do focal HIFU on all areas that are positive for cancer.

With improved cancer mapping using high-resolution PET/MRI, we hope to be better at treating the cancer completely. By maximizing our imaging, we hope to maximize the cure rate.

What sort of follow up are you doing after the focal therapy?

Dr. Daskivich: At six months after focal therapy with HIFU, patients get another prostate MRI and targeted biopsy in both the treated and untreated zones. We also follow with serial PSA levels.

Do patients need to come to you for the initial imaging and HIFU?

Dr. Daskivich: Patients come to us already having been diagnosed with prostate cancer on biopsy. We then do the high-resolution PET MRI and repeat targeted biopsy based on the advanced imaging at Cedars Sinai. Patients who remain eligible and interested in HIFU go on to get this treatment at Cedars Sinai.

Do they need to come back to your center for the follow-up MRI and PSA testing, or can they do that at a remote location?

Dr. Daskivich: Yes, patients do need to do follow up MRI and targeted prostate biopsy at 6 months at Cedars Sinai. PSA testing can be done at a remote location if necessary.

Is there are any fee to patients for participating in the trial?

Dr. Daskivich: All procedures that are not standard-of-care are funded by the trial. This includes the high-resolution and PET components of the MRI. Importantly, though, the HIFU is an out-of-pocket cost for participants, since it is a standard of care procedure and we’re studying the imaging and not the HIFU procedure itself.

Is all the follow-up covered?

Dr. Daskivich: Most often, insurers cover follow up imaging for prostate cancer treated with HIFU as standard of care.

Any particular eligibility criteria you’d like to highlight?

Dr. Daskivich: Participants on this trial must either have clinically localized, unilateral high-grade (Gleason 7 or higher) or high-volume Gleason 6 (>50% of cores involved) disease. Those with unilateral high-grade disease can also have contra-lateral low-grade (Gleason 6) disease, but they cannot have bilateral high-grade disease. PSA must also be less than 20.

We specifically designed the study to exclude patients with low-volume Gleason 6 disease (<50% percent of the cores involved). This is because active surveillance is a better treatment option for most patients with low-volume, low-risk prostate cancer.

Any final thoughts or advice for patients?

Dr. Daskivich: I was initially a skeptic about focal therapy, and that’s why I wrote this trial. I wanted to document all of the outcomes in a very systematic way and convince myself that it was effective. Having used focal therapy with HIFU for some time now, I’ve been pleasantly surprised at how effective and minimally morbid it is, at least in the short term. Cancer control has been excellent in the short term and the side effect profile is much better than traditional therapies like surgery or radiation. HIFU is done as outpatient treatment as well, so it is also convenient. It’s honestly quite refreshing to have a prostate cancer therapy that doesn’t come along with the traditional baggage of urinary incontinence and erectile dysfunction.

Which can be debilitating.

Dr. Daskivich: Which can be very debilitating, even if it is experienced for only a short period of time. If the long-term cancer control of focal therapies for prostate cancer like HIFU turn out to be durable, then it could change the standard-of-care for unilateral high-grade disease. Time will tell.

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Dr. Scott Eggener on Focal Therapy for Prostate Cancer

Scott Eggener, MD, an internationally known robotic and open surgeon, specializes in caring for patients with prostate, kidney, and testicular cancers.

He is the Director of the Prostate Cancer Program and Co-Director of the High Risk & Advanced Prostate Cancer Clinic at University of Chicago Medicine.

Prostatepedia spoke with him about focal therapy for prostate cancer.

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Why did you become a doctor?

Dr. Scott Eggener: I came around to medicine later than most people. I always had an interest in science and math. The combination of being able to use those skills to help people out and to have a component of life that combines clinical care with research was ultimately the attraction that led me down this path.

Have you had any particular patients whose cases changed either how you see your own role as a doctor or how you view the art of medicine in general?

Dr. Eggener: I try to learn regularly from my patients. The overwhelming majority of cases are fairly routine from a medical standpoint, but what makes my role fascinating are the unique elements of their background or hobbies and getting to know them.

As far as memorable experiences, there are so many standouts from both the really heartwarming celebratory side and the profoundly depressing side. When you have a practice that focuses exclusively on cancer, you’ve got the highest of highs and the lowest of lows.

What is focal therapy? Where does it fit into the spectrum of treatments available to men with prostate cancer today?

Dr. Eggener: Focal therapy is a dense topic. The bird’s-eye view is that, traditionally, any treatment of prostate cancer localized to the area of the prostate is focused on the entire prostate. Unfortunately, the prostate is in ground zero of the pelvis where there are a lot of other important structures. Any treatment, even when done by a very experienced specialist, poses a risk of short and long-term side effects. The first and most important fork in the road is whether the cancer even requires treatment. Active surveillance, monitoring the cancer, is a very attractive approach for many men with an extremely low-likelihood of cancer-related problems.

The concept of focal therapy is to only treat the part of the prostate that has the cancer and leave the rest of the prostate alone with the utopian dream of limiting the risk of cancer-related problems while trying to optimize the quality of life and minimize exposure to side effects. It’s analogous to women with breast cancer. There was a time when every woman with any type of breast cancer had a radical mastectomy. Through good science, clinical trials, brave patients, and data nowadays, somewhere between 65 and 80 percent of women get a lumpectomy. We’re in the very early stages of determining whether a similar strategy is safe and smart for some men with prostate cancer.

There are different forms of focal therapy: are some forms more effective than others?

Dr. Eggener: There are literally about a dozen different ways of ablating a part of the prostate.Focal therapy is a concept of treating part of the prostate. There are a lot of different mechanisms of trying to destroy parts of the prostate. There is not enough comparative data to say A is better than B or C is worse than D. There are some focal therapy interventions that have been studied relatively rigorously. Most have been studied in small populations of men. None have sufficient longterm follow-up, and none have ever been sufficiently compared to surgery or radiation therapy, which are the conventional and time-tested treatment options.

Is that one of the controversies over focal therapy—that there’s not enough long-term data to know which is better or not?

Dr. Eggener: There are a gazillion different reasons why focal therapy is controversial. Number one is that focal therapy turned the whole paradigm on its head in that prostate cancer is typically multifocal where about three-quarters of men with prostate cancer have multiple cancers within their prostate. Reflexively, a lot of people feel the entire prostate needs to be treated.

What we know based on elegant studies is the overwhelming majority of those other cancers within the prostate are not destined to cause any problems. There are many prostate cancers that are indolent, and if they are destined to cause problems, it’ll be years or decades down the road. Some people are fundamentally opposed to the concept of treating part of the prostate. There isn’t enough high-quality, long-term data to show whether the focal therapy paradigm is beneficial for certain men.

Conceptually, it’s supposed to be helpful, but until we have proper clinical trials, that’s just speculative. That is why there are dozens of clinical trials. Hopefully, one day we’ll have quality data. There have been a lot of companies interested because it’s attractive to patients.

The FDA has recently gotten more engaged. There have been multiple public meetings with the FDA trying to figure out how best to evaluate focal therapy. There is a swell of interest, but it’s going to take thoughtful investigators to provide the data. Unfortunately, as you know, in the landscape of prostate cancer there is often a lot of enthusiasm without data supporting it. Unfortunately, there are always charlatans willing and capable of putting the cart before the horse.

Is there anything about focal therapy that would prevent a man from getting a later treatment—i.e. a radical prostatectomy or radiation therapy?

Dr. Eggener: Conceptually, the plan is to do focal therapy and it doesn’t necessarily burn any bridges. Theoretically, the more time that passes there is an increasing chance that in certain men the cancer can spread elsewhere in the body, although if you select men well for focal therapy you can minimize those risks. Depending on the type of focal therapy that’s used, some have close to no impact on the efficacy of future treatments. There are other forms of focal therapy that are more aggressive and would impact the possibility of doing surgery or radiation in the future.

Do you have advice for men reading this who might be considering focal therapy?

Dr. Eggener: It’s exciting conceptually but we’re still in the very early stages of properly evaluating this approach. There are a range of practitioners who will offer focal therapy from very thoughtful prostate cancer experts with very selective criteria, clinical trials, and tempered enthusiasm to those on the other end of the spectrum—people who are one trick ponies who believe nearly every man they see might be a candidate for focal therapy.

My advice to people is if you’re newly diagnosed with prostate cancer and think focal therapy might be an attractive option for you, seek out someone who has expertise in prostate cancer who offers focal therapy amongst many other options and can thoroughly discuss the knowns and unknowns.

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