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Conversations With Prostate Cancer Experts


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NRG Oncology’s Clinical Trials

Dr. Mark Hurwitz, a widely recognized leader in the fields of thermal medicine and genitourinary oncology, is the Vice-Chair for Quality, Safety and Performance Excellence and Director of Thermal Oncology for the Department of Radiation Oncology at The Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia, Pennsylvania.

Dr. Hurwitz talked to Prostatepedia about NRG Oncology and a trial he’s running with them that looks at anti-androgen therapy and radiation therapy with or without Taxotere (docetaxel) in treating patients with prostate cancer that has been removed by surgery.

Why did you become a doctor?

Dr. Hurwitz: Medicine is an extraordinarily rewarding career in regards to being able to help people at important and often critical junctures in their lives. It’s extremely humbling to see strangers walk into my office and put their trust in me to help them through a difficult time in their lives.

It’s an enormous responsibility.

Dr. Hurwitz: It is, but one that comes with many years of training and preparation for a physician to get to the point when we enter practice.

What is NRG Oncology? What has been your involvement with the group?

Dr. Hurwitz: Several years ago, the National Cancer Institute (NCI) mandated the merging of cooperative cancer research groups into fewer but larger groups. One of these groups NRG Oncology, was the result of the merging of the Radiation Therapy Oncology Group (RTOG) with the Gynecologic Oncology Group and the National Surgical Adjuvant Breast and Bowel Project (NSABBP). This dynamic new large cooperative research group is primarily supported by the NCI. It’s been exciting and rewarding to be a part of this new larger group putting all our resources together to bring trials to patients.

I’ve been involved with NRG Oncology since its inception. Predating that, I was involved with both RTOG, as well as the Cancer and Leukemia Group B (CALGB) during my years at Harvard Medical School.

What kinds of trials does NRG oncology run?

Dr. Hurwitz: The focus of cooperative groups, including NRG Oncology, is on conduction of clinical trials to answer important questions that are best addressed by getting multiple centers involved. These tend to be Phase II or Phase III trials involving hundreds, and sometimes thousands of patients, to answer a critical question that experts in a given field see as being one of the most impactful issues to address for a given set of patients.

NRG is also involved in translational science as well. Almost all of our clinical trials have an incorporated translational aspect to them to answer leading-edge questions in regards to some of the pertinent science behind advancing treatment for our patients.

Are the participating institutions limited to within the US?

Dr. Hurwitz: There are international participants. The group does have a North American focus. Therefore, the United States, as well as many Canadian institutions, are very active in NRG, but NRG has branched out to include international institutions outside of North America as well.

Is it difficult to enroll patients in trials?

Dr. Hurwitz: We all in academic medicine seek to engage more patients with involvement in clinical trials. Only a small percentage of patients nationally participate in clinical trials, so there’s a real opportunity to match patients and their needs with the clinical trials that will help advance the field, as well as their own personal care.

Some of the challenges include having appropriate trials available for patients seen within a practice, as well as the time commitment both in terms of the extra time that the physician needs to take to explain trials as well as the resources needed to support the conduction of clinical trials at a given site.

There is also the issue of awareness both on the patient and provider sides as to opportunities for clinical trial participation.

Why should patients consider joining the clinical trial?

Dr. Hurwitz: There are several reasons for patients to consider trials. A trial often provides patients access to leading-edge therapeutic strategies that may not be available off clinical trials.

It also will help provide additional information that will benefit future patients, although our focus is always on the patient who is sitting in front of us.

Also, interestingly enough, there are multiple studies that have looked at the impact of clinical trial participation on patient outcomes, with very consistent findings that patients on clinical trials tend to have better outcomes including survival outcomes than patients not on clinical trials. This is likely due to a number of factors, including the rigorous monitoring of patients on clinical trials as well the follow up after treatment that is done. These patients are followed very closely. There are state-of-the-art treatment guidelines that must be followed on clinical trials to help reduce undesirable variability in patient care. These aspects of clinical trials help to improve outcomes regardless of the particulars of any clinical trial.

Are there certain stages along the cancer journey when a patient should consider a trial?

Dr. Hurwitz: There are clinical trials that are suitable for patients across the whole spectrum of disease severity. In the case of prostate cancer, there are trials for patients with very favorable risk disease for which active surveillance is an option to trials for patients who are on second or third line interventions for metastatic prostate cancer. And everything in between. It’s not a matter of whether a patient has a certain stage of disease. There are questions to be answered at each stage of a given disease for which clinical trials may provide benefit.

Are there any considerations patients should keep in mind as they evaluate trials?

Dr. Hurwitz: People have to gauge the particulars of a trial much like the particulars of any proposed treatment for malignancy in regards to what makes them most or least comfortable with the options before them.

Let’s say a patient participates in an NRG trial. Are they informed of the results once the trial is completed?

Dr. Hurwitz: There have been increased efforts in recent years to disseminate outcomes of trials to patients. It’s a particular challenge in some diseases like prostate cancer where the results may come a decade or more after trial participation.

That’s true.

Dr. Hurwitz: There is an effort regardless of the outcome of the trial to make not just practitioners but patients aware of the results.

Are there interesting NRG prostate cancer clinical trials that you’d like to highlight?

Dr. Hurwitz: I’m happy to highlight NRG-GU002, for which I am privileged to serve as the principle investigator. This trial builds on a prior Phase II single-arm RTOG trial, RTOG-0621, which I led that revealed very promising outcomes with the addition of Taxotere (docetaxel) and hormonal therapy to radiation for patients with adverse risk factors post-prostatectomy. NRG-GU002 builds upon the single-arm Phase II trial as a randomized Phase II into Phase III trial exploring the use of radiation and hormonal therapy with or without Taxotere (docetaxel) in men who fail to achieve a PSA nadir of less than 0.2 nanograms per milliliter after prostatectomy. This is a particularly high-risk group of patients in regards to risk of subsequent treatment failure. We have been very encouraged by the efficacy of Taxotere (docetaxel) in treating prostate cancer. Taxotere (docetaxel) has been shown initially in metastatic prostate cancer and subsequently in locally advanced disease to have a survival advantage—as opposed to using radiation or hormonal therapy alone in the primary treatment setting. Therefore, there is a lot of interest in exploring its utility in the post-prostatectomy setting for high-risk patients.

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Jake Vinson + The Prostate Cancer Clinical Trials Consortium

Mr. Jake Vinson is the CEO of the Prostate Cancer Clinical Trials Consortium (PCCTC), a multicenter clinical research organization that specializes in trailblazing prostate cancer research.

Prostatepedia spoke with him about clinical trials for prostate cancer and the pioneering work of PCCTC.

How did you get involved with clinical research administration and patient advocacy?

Mr. Jake Vinson: My involvement in clinical research dates back to college years. My part-time job was working in a clinical research organization, and I really enjoyed that environment and the work that was a being done. I progressed through college and graduate school and subsequently was able to run a number of clinical research organizations. That process brought me to New York about ten years ago to be involved in the Prostate Cancer Clinical Trials Consortium.

As far as patient advocacy, I’ve grown to distinguish two threads of advocacy, one being patient advocacy and the other being research advocacy. My path in working through drug development and clinical trials has really been geared more toward research advocacy than patient advocacy.

Patient advocacy considers needs at the individual patient level —ensuring they’re getting to the right appointments and having the right tests and seeing the right experts. Research advocacy makes certain research is funded appropriately. It ensures that research is being watched over in the right way and that it intersects with the patient advocate component. It’s an interesting distinction, but one that I think is important.

What has kept you engaged over the years?

Mr. Vinson: I’ve always found the organizations that I’ve worked with and have run sit in a very interesting and unique spot in the continuum of cancer research in that they connect academic investigators who are the subject matter experts; they think about new ways to develop drugs and treat patients; and they connect them with the pharmaceutical and biotech companies who are developing drugs aligned with the scientific programs of investigators. And finally, there is the part that we talked about—the advocacy component. Making sure that patients at the clinical sites where they’re being cared for have access to these research studies.

What’s kept me involved is being in the middle of that triangle. Not necessarily working in a hospital or in an academic research center. Not necessarily working in a pharmaceutical company. And not necessarily working at a clinic site or a doctor’s office, but really creating an infrastructure that connects all of those things. That to me has been exciting.

What is the Prostate Cancer Clinical Trials Consortium?

Mr. Vinson: The Prostate Cancer Clinical Trials Consortium (PCCTC) is an organization that has been around for going on 20 years now. It was originally created by the Prostate Cancer Foundation (PCF), which is the world’s most significant philanthropic prostate cancer research-focused organization. They recognized that there were obstacles in the collaboration of what were considered the top prostate cancer academic programs around the United States. They worked to put some funding in each of those centers with the sole goal to eliminate barriers to working together on clinical trials. This was some time ago.

That idea was subsequently leveraged into an initiative through the Department of Defense [DoD], which here in the United States has the Congressionally Directed Medical Research Program. Within that program is the DoD Prostate Cancer Research Program (PCRP).

Fifteen or so years ago, the PCRP put in place an offering for a Clinical Consortium Award. This was a formalizing effort to PCF’s idea. Memorial Sloan Kettering Cancer Center (MSK) applied for and became the coordinating center for this Consortium Award. Eight other centers were selected as participating sites. This created the coordinating center site model, or a consortium, to bring together and understand what clinical trials everyone was working on, where the intersects were, and where the collaborations across sites could happen efficiently and effectively. The aim was to shape and understand the landscape of prostate cancer drug development to take out those preconceived notions of competition and show areas where cooperation could happen.

MSK still holds that Clinical Consortium Award. We’ve had a number of sites come in and out over the last fifteen years.

A number of years ago we identified that to really be effective and to scale our infrastructure to support all kinds of prostate cancer research we needed to have a better business-operating model than something based solely on a grant from the from the DoD.

So, just over five years ago we spun off a business, which is now the operating company for the PCCTC. That business exists to conduct multicenter clinical trials so that all of our participating sites around the world now can work together on selected clinical trials. We let the investigators do what they do best, which is develop the ideas and ways to study the drugs. We let the clinical research sites and the clinics do what they do best, which is treat their patients and manage them on a study. This in turn lets us handle the regulatory, data, and biospecimen management—all of the things that go on behind the scenes of a clinical trial that investigators and sites aren’t specifically suited to address. Through contracts with our pharmaceutical partners we are able to get access to their drugs that are developed by the pharmaceutical companies and then put those into the clinical trials that our investigators are developing. That is how our model works.

That’s a unique model, isn’t it?

Mr. Vinson: It is fairly unique. It has attributes from a number of different businesses in this space. It in and of itself functions in a fairly unique way.

What kinds of clinical trials do you run?

Mr. Vinson: The organization was originally established as an early phase drug development group, so our intention is to identify new drugs, new classes of drugs, or new targeted drugs to treat prostate cancer patients of all stages. We do very early studies with patients who are newly diagnosed or often times we do studies with very late stage patients who maybe have seen a number of lines of treatment already.

We really look at the continuum of disease states from very early diagnosis to very advanced disease. We identify which studies would be most reasonable to put in place in all of those spaces so that we’re not necessarily constantly overlapping. We want to have studies distributed fairly evenly so that patients of all different disease states or manifestations within states would have an opportunity to be in a clinical trial if treated at one of our sites.

We have traditionally focused in Phase I and Phase II development. Because we’ve been fairly successful in that, we have now opened our first Phase III study, which is a much larger trial. A Phase I or a Phase II trial has from 30 to 100 patients. A Phase III study can have as many as 800 to 1000 patients.

I’ve heard that it’s difficult to enroll patients in trials and that frequently trials don’t get the number of patients they were originally seeking. Why do you think this is?

Mr. Vinson: There is data that shows this is absolutely true. What we know is that, in the United States, 3 to 5 percent of cancer patients go on to clinical trials, which is obviously not very many. Even within the number of eligible patients, only 25 percent actually do enroll in a clinical study.

I should also add that because of the way the science has taken us, we are now looking to enroll patients with specific molecular characteristics. These molecular characteristics are biomarkers, or gene signatures that we see in tumor tissues or blood, which can often be found only in a very small percentage of patients. A particular marker that we think a drug works in may only appear in 10 or 15 percent of patients. A fairly small group of patients go onto studies to begin with; molecular inclusion criteria makes this number smaller.

This is creating a conundrum whereby we have to cast a much wider net, meaning we have to have more sites collaborating to identify patients eligible for enrollment based on their unique molecular characteristics. These are interesting challenges. The science to be able to do this is incredibly significant and will be impactful to patients, but filling those clinical trials is difficult. We would think we would want to include more patients in studies, but because we’ll be able to parse the patients into much smaller groups with specific molecular characteristics, it is becoming more challenging.

You need to cast an even wider net to find these patients?

Mr. Vinson: That’s exactly right. We originally worked with eight centers. We now have 14 centers that are formally part of our group with another 50 sites in the United States who are affiliate participants. Those centers have gone through our qualification process; we know they have quality research programs at their clinical sites and have the opportunity to open studies that we’re developing as well. That is one of our strategies, to circumvent that conundrum of great science that then doesn’t enroll the patients we planned.

There are some regulatory implications here: there has to be great caution in doing clinical research. We would offer that, when you’re using drugs in a very early development space, meaning this is often the first time that the drug has been used in patients, you want to make sure that the patients are appropriate to be treated with those drugs. What you can’t do is just flood your study with patients because you might miss a safety signal, or you might miss a dosing change. There are too many variables happening at the same time. We know that is part of the issue.

From the other end, it’s a lot of work for the clinical sites to participate in the studies. We do our best to fund our sites appropriately, but there are so many pressures on our clinicians in terms of how they’re managing their electronic medical records and how many patients are expected to be seen by their clinics and their sites. Their additional bandwidth to enroll patients under clinical trials is finite. You have to consider all of the safety and regulatory requirements for the studies themselves and the external factors for the investigators working on the studies.

Finally, we and others have been working for a long time on research and patient advocacy.

When a patient comes in and they’re approached about a clinical trial, we don’t want that to be the first time they’ve ever heard about clinical research. That’s an entire other discussion that requires a full education to make folks comfortable with clinical trials. Those are the three angles that we try to work on in alleviating those barriers.

Why should patients consider joining a trial? What are some of the benefits?

Mr. Vinson: Depending on the study, the potential for benefit can vary. There are potential advantages to getting access to a new drug, which could in theory have great benefit to them, but again, this is called research. We don’t know exactly what the outcome will be, but there is the opportunity to get access to more cutting-edge treatment that could have an upside.

The other lens to think about is that research is advancing the field for the men who will follow. If we didn’t have the clinical trials that we did 25 years ago, we wouldn’t have the drugs that are now proven to extend life . There were men who joined clinical trials to get those drugs approved and tested as safe and efficacious or that worked in controlling cancer. We would offer that there’s great opportunity to, in a safe way, contribute to the advancement of treatments for future generations of men. We think that’s important.

Is there a certain time point when a man should start looking for clinical trials?

Mr. Vinson: Ideally patients should learn about the clinical research process at the point of diagnosis so they understand the advantages and risks of trial participation. Men should feel comfortable asking their healthcare providers about clinical research opportunities at any point in their care.

From a drug development perspective we traditionally evaluate therapies earlier in the disease continuum only after establishing efficacy in more advanced disease. We think there is potential for a cure in very early disease and are now designing trials of drugs that gave benefit in very advanced disease in this space. We really feel like there needs to be clinical research participation from very early on while we continue to look to control disease that has spread and become more advanced. In short, there are opportunities to participate in clinical trials starting at all points of care.

I suppose if you start a conversation early on with your doctor, even if there’s nothing appropriate for you at that time, if something does come up, she is more likely to bring it to your attention.

Mr. Vinson: Absolutely. Opportunities are continually turning over: new studies are opening and prior studies are closing. We know patients from all over the country who have been on multiple clinical trials. Many do very well. We think it’s exciting that they’re open to that.

Do you have any suggestions that you think patients should keep in mind as they evaluate trials?

Mr. Vinson: There are so many different types of studies out there. I think a Phase I study may have requirements in it for some additional testing or additional visits because the endpoints of that kind of study are to evaluate at very specific timepoints how a drug is being received and metabolized or processed by a patient.

The bigger and later stage Phase II or Phase III studies are designed to be as continuous with standard of care as possible so that it is not a burden or inconvenience to the patient. All of those things have to be taken into consideration. An honest discussion with your healthcare provider, healthcare team, and the research coordinator or research nurses, is really the best way to figure out which situation is going to be best.

How the results of your trials are reported? Are all trials reported? Are patients who participate in trials informed of the results?

Mr. Vinson: We publish and present all the results from our research studies. We ensure that we have the right to do that with our partners —our research sites and our pharmaceutical and biotechnology partners as well as the groups that own the drugs that we work on. We have contracts with them that are very clear in that we have the ability to put the data together, to put the outcomes together, and present them to the public. That’s done through a number of different methods— meetings where abstracts are presented to manuscripts submitted to professional journals.

Your point is a good one about returning results to patients. Many sites have programs to distribute the outcomes to those patients. This is done at the site level. The challenge for us is that we don’t get, in almost all cases, direct contact information for patients. When a patient goes on a trial, the local treating clinicians certainly know that patient well. But we give that patient what we call a subject identifier. This is a random number that is created so that we can then track that patient without having any personal information about the patient directly. We have their health outcomes data, but we certainly don’t know where they live, or what their phone number is, or how to email them. Returning those results directly to a patient from the entire study as you can imagine, is something that would be challenging.

Informed consent forms reflect the growing number of molecular testing and sequencing performed in trials. Before patients participate on a trial they are clearly notified on of which test results would be returned to them personally. This can vary from study to study.

But to your point, we think it’s important when we’re doing research tests that could have implications for a patient or their families, especially when we’re talking about genetic testing, that we have a mechanism to inform them if there are findings that need to be followed up. As you can imagine, there are implications for family members as well in genetic research. That happens through the informed consent process, and again, at the site level where the patient’s being treated.

I guess if you’re going to make a call for men to join trials for altruism’s sake and for the furtherment of science, they might want to know if the research actually did advance our understanding of prostate cancer.

Mr. Vinson: There are sites that do that: when outcomes are published, they distribute them to patients who are interested. In addition, publications can be searched for independently or requested from the clinical investigator.

It takes a long time for some of these studies, though. If you’re the first man to go into a particular study and it’s going to be a 100-patient trial that takes over a year, you’re already taking about 18 months to enroll that study. Then we do all the follow up, which could be another two years. Then we do all of the data analysis, which could be another six months. It could be three to five years from the original patient enrolled to publication. It can certainly be a long process.

Are any particular PCCTC trials looking for patients that you’d like to highlight for my readers?

Mr. Vinson: We’re doing a study called IRONMAN. IRONMAN is an international registry for men with advanced prostate cancer. We’re working with eleven countries around the world in collaboration with the Movember Foundation. (Movember is the Australian-based organization that grows mustaches and raises money every November for men’s health and awareness.) One of their core programs is a prostate cancer program, and one of their key projects is the IRONMAN project.

The PCCTC is the global coordinating center for IRONMAN. The study does not have a specific drug treatment requirement and instead tracks patients receiving standard of care therapy. Participants will be recruited across academic and community practices from around the world to facilitate a better understanding of variations in prostate cancer treatment. Patients who enroll are followed prospectively over several years. We collect data on what treatments their physicians have given them as well as some high-level clinical outcomes data from those treatments and track how treatments are sequenced or given in combination around the world.

The second part of the trial examines patient reported outcomes. We have particular surveys that study participants complete every three months that examine their quality of life and how they’re feeling across a number of domains. Then thirdly, we have a biology component, in which we collect blood samples when patients join the study and then again each time they change their treatment. This helps us understand, to the point I was making earlier, what changes are happening at the molecular level and what’s changing in the biology of the patient. Then finally, we’re asking their physicians to answer a brief survey telling us why they recommended changes in treatment, which will give us insight into the variations in prostate cancer treatment across different centers and countries. By collecting blood samples, patient reported outcomes, clinical data, and physician surveys, we can tie together the biology of the patient’s disease with the patient’s reported experience on a given treatment with the clinical data on their response to treatment. Putting all of those things together with 5,000 men around the world in eleven countries is going to give us an incredibly rich dataset to be able to mine and understand what treatment patterns may be best for particular patients. What’s unique about IRONMAN is that we are not just collecting information on how patients do clinically, but also how the patients themselves report they do. Through IRONMAN, we will also understand the biology of those patients and how it changes over time, and we will be able to tie those outcomes to the clinical outcomes to develop tests that can potentially let us predict how patients will do on a specific treatment.

IRONMAN is an exciting study. Centers around the world are now open and actively participating in the study. We have nearly 700 patients accrued from 7 countries, with 4 more coming on board soon. It’s an exciting project, and something that is very different than a standard Phase I or Phase II clinical trial, but it’s certainly something that we think is going to result in an incredibly powerful dataset for investigators to use into the future.

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Prostate Cancer Clinical Trials

In May, we’re talking about clinical trials for prostate cancer patients. Not a member? Join us.)

We also have an ulterior motive: we would love it, if after reading this issue, each and every one of you asks your doctor if there is a clinical trial that is appropriate for you. Why? Clinical trials are the only path to furthering our understanding about how and why prostate cancer occurs—and progresses—in some people and not others. It’s also the only way we can develop new and better ways to treat prostate cancer.

But all of that is lofty and altruistic.

How do you, as an individual patient, benefit from joining a clinical trial? First, you may be able to access treatments, procedures, or imaging that you would not otherwise be able to access.

And even if you’re on the control arm of a study, you’ll get standard of- care, which could mean drugs, scans, or procedures at a reduced cost. At the very least, when you join a trial you will be more rigorously monitored by the study team, which could lead to better outcomes for you. Studies show that patients on clinical trials tend to do better than those not on clinical trials, even if they get the same treatment.

When should you consider looking for a trial? Right after you’re diagnosed. Just ask your doctor if there are any trials that are right for you. There may not be. But by asking, you’re letting her know that you’re interested so that, the next time she runs across a trial looking for patients like you, she’ll be sure to bring it to your attention.

Once you enter a trial, make sure you let the investigators know that you’re interested in the results.

Of course, given both prostate cancer’s long natural history and the clinical trial process, those results may not come for many years after your actual participation, but let the researchers know that you’d like to know the results once they’re available.

As you’ll read in the conversation with Ms. Merith Basey, too many clinical trial results go unreported in the United States and on a global scale. How can you help? As Ms. Basey points out, if you graduated from a United States university, call or write your alma mater to let them know that you’d like the administration to ensure that every trial conducted under their auspices is reported—whether those results are positive or negative.

Join us to read this month’s conversations about clinical trials.


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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. Hashim U. Ahmed on Today’s Focal Therapy For Prostate Cancer

Dr. Ahmed is Professor and Chair of Urology at London’s Imperial College Healthcare.

His research focuses on prostate diagnosis using novel imaging and tissue biomarkers, prostate treatments that reduce the harms of traditional surgery and radiotherapy, and clinical trials and health technology evaluation.

Prostatepedia spoke with him about the current state of focal therapy for prostate cancer.

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What is focal therapy?

Dr. Ahmed: Focal therapy is about targeting the tumor within the prostate with a margin of normal tissue. The tumor is one that we believe that were we to leave it untreated, would progress, grow and spread, and impact the patient’s life at some point. By doing so, we avoid treating the entire prostate. We avoid damaging as much normal little tissue as possible. By damaging as little tissue as possible, we aim to maintain as much function as possible for that particular man, whilst at the same time treating the cancer that would otherwise cause problems in the future.

What are some of the various forms of focal therapy? Focal therapy is an umbrella term, is it not?

Dr. Ahmed: It is an umbrella term. I often joke that there’s almost like a catwalk of treatments that can be used for focal therapy. The traditional ones were cryotherapy, which freezes the tissue, and high intensity focused ultrasound (HIFU), which uses very focused ultrasound waves that heat up the prostate. You can use laser, which also heats up the prostate. You can use electrocution of the cells, which is called irreversible electroporation. There are now some new injectable drugs. You can inject hormone drugs or molecules that are activated by PSA, which then kill the prostate cells once they are injected into the prostate. There’s a lot of activity going on.

What I often say is that all of these different modalities are interesting. It’s good to see that commercial bodies are really interested in this field. That shows that the concept has real legs and everybody sees this as a big future, so that everybody’s crowding into the market. Ultimately, these are all tools, if you like— surgical instruments for me to do my focal therapy. No one tool can be applied to all tumors.

Let me take an example. If you had a big prostate with a tumor high up in the gland, there’s no way HIFU would be able to reach it. The ultrasound wave just can’t get that far. Even if it could, by the time it reached the tumor, there would be so much tissue it went through that it would lose its energy. For that particular tumor, an anterior tumor, something like cryotherapy is probably going to be better for that particular man than HIFU. A posterior tumor near the rectum, but contained in the prostate, probably does really well from HIFU at the moment, but could easily be treated in the future using these injectable drugs, if they’re to be efficacious.

Which form of focal therapy is best really does depend on where the tumor is, how big it is, and how big the man’s prostate is. Are there other characteristics within the prostate, for instance, like calcification, which means you can’t see the tumor? Those calcifications might, potentially, deflect the energy. There are a lot of other considerations, but there are quite a lot of things that you can use. I would say the two that are in pole position at the moment, just because they’ve been around for longer and therefore they have a lot of data, and the two that I use routinely in clinical practice, are HIFU and cryotherapy.

For which men is focal therapy usually an appropriate choice?

Dr. Ahmed: Firstly, focal therapy is a choice for the man who wishes to preserve or minimize his risk of genitourinary side effects like incontinence and erectile dysfunction as much as possible. You could argue that everybody wants that, but there are some men who will just have radical treatment and say to me, “I understand that I have side effects, but I just want it sorted out.” There are other men who prioritize minimizing the genitourinary impact that treatments have.

Focal therapy is also a good choice for men who have one index lesion. In other words, they have one tumor that is clinically significant, but at the same time have either no other tumors or one or two clinically insignificant cancers. In those men, we would target the main, biggest, or highest grade tumor because that is the one, studies have shown, that is likely to grow, progress, and metastasize if it was left on its own. The other, smaller, low-risk lesions are the type of indolent disease that a lot of men in the male population have that doesn’t need immediate treatment. You can monitor those after you’ve knocked out the main tumor, for instance.

You wouldn’t want to just knock out those one or two insignificant cancers while you were in there anyway because of potential side effects?

Dr. Ahmed: One of the reasons is it’s difficult to localize one or two millimeters of low-risk disease. In order to treat those, you’d have to end up treating a block of tissue. By the time you’d treated that block of tissue, or two other blocks of tissue, you’re probably at 70 to 80% of the prostate volume.

And if you do that, you might as well just target the whole thing?

Dr. Ahmed: You might as well just treat the whole thing because you’re going to cause as much damage. These small lesions are often not visible on MRI. They’re found on random, systematic biopsies, and you have no idea exactly where they are.

Another consideration is the characteristics of the lesion itself that we would want to treat. It could be one of two things: intermediate Gleason Grade 7, so 3+4 or 4+3. Or, there’s an increasing recognition that high volume Gleason Grade 6 is also something that is better treated immediately than monitored because that is also likely to progress.

For unfavorable, if you like, low-risk disease and intermediate-risk disease where there is one index lesion you can carry out focal therapy. If you can have intermediate-risk disease, which has two or three significant lesions, you would be better served having radical therapy.

What happens if a man gets focal therapy and later his cancer recurs? Can he go on to other subsequent treatments?

Dr. Ahmed: This is quite an important topic now. We know that following focal cryotherapy, focal HIFU, and some of the newer emerging focal therapy modalities that about 15 to 20% of men will either have residual or recurrent disease in the area that’s already been treated. Most of those men will be eligible to have a repeat session of HIFU or cryotherapy. Certainly in my practice, I tell men there is a one in five chance that we may have to repeat the focal therapy to the same area. Almost invariably, all men see that as just part of the intervention. I would argue having two treatments in a fifth of men is probably part of the treatment.

If they fail two treatments in that area, then they really should go on to have radical therapy, or a change in the type of treatment that you give. If the cancer has resisted 80 to 90 degrees centigrade temperature changes twice, or with cryotherapy minus 50/minus 60 degree centigrade twice, then that is an aggressive tumor. It probably has got a very aggressive blood supply and we need to change tacks.

There is a group of men who develop new lesions in untreated tissue. Some of those men can have another focal therapy, but most of them will go on to have radical therapy because their untreated tissue, if you like, has declared itself as unstable. It has a propensity to develop new tumors, and therefore, it would be better to treat the entire prostate.

About 15 to 20% of men over five to six years need a second focal therapy treatment. Overall, about 5 to 7% of men go on to have radical therapy, despite one or two focal therapy sessions. Now that is five to six-year data; we don’t have ten-year data at the moment, either from HIFU or cryotherapy. The newer modalities don’t even have five to six-year data.

Is it safe to say focal therapy is still an emerging option and that we still don’t have all the data?

Dr. Ahmed: I guess it depends on how you define that level of evidence. If we have to wait ten to fifteen years, then yes. If you argue that we’ve now got good five to ten-year data showing non-inferior cancer control, superior toxicity, or superior side effect profiles after focal therapy, then there are a considerable group of men who will accept the uncertainty of the lack of ten to fifteen-year data. They prioritize genitourinary function and they are not compromising their cancer control, at least at five to six-years median follow-up. And they can still have surgery or radiotherapy afterwards.

In the United Kingdom, in certain centers, focal therapy has been offered side by side with other radical therapies within the National Health Service, as part of the NICE, or National Institute for Clinical and Healthcare Excellence, approvals that we have.

What are some of the other controversies over focal therapy?

Dr. Ahmed: There are a number of controversies. One big controversy is this lack of ten to fifteen-year data. I was in the European Congress a couple of days ago. There was a Pro/Con focal therapy argument. I was pro and the person before me was con. He stood up and said, “We don’t have fifteen to twenty year data.” Five years ago, we didn’t have five-year data. A couple of years ago, it was you don’t have ten-year data. When we first started, they said well you don’t have any one year data on biopsies. This is the first time I’ve heard people stand up and say, well you don’t have fifteen to twenty-year data. It’s slightly amusing. It’s infuriating, as well, because the goalposts keep on changing. The long-term data will come; we’re collecting all the data in registries in the United States, the United Kingdom, and European centers. It’s all very robust data collection. We’re doing trials to see if men will accept randomization between radical and focal therapies. Those trials are tough. Men generally want to choose their therapy rather than allowing themselves to be randomized, but we’ll see.

Then the other controversies are around the areas that we touched on. What happens to the untreated tissue? So far, about 4 to 5% of men over the five to six years of median follow-up that we have in our series of several hundred cases have developed new lesions in untreated tissue. Now, those are probably just tiny bits of Gleason 7 tumors that the biopsy and MRI missed that then subsequently progressed. Some of them will be new lesions, but some of them will be disease that was missed in the first place, which declare themselves later. By ten years, it might be higher. So far it’s quite low.

One of the arguments against focal therapy is that this is a multi-focal disease. The untreated tissue is just going to show up with lots and lots of cancers, but that has not been the case, so that has been quite reassuring. The other controversy is around the point that MRI is not good enough and biopsy is not good enough. But I think both MRI and targeted biopsy are good enough. You can never be 100% in anything. If you look at breast mammography, the data shows that a negative mammogram can miss anywhere between 5 to 30% of breast cancers, yet we still use it as a screening tool. We all accept that nothing in medicine is certain. Then there’s concern about what happens to men who fail focal therapy. Can we remove the prostate, or are these men too scarred. What happens in terms of their cancer control? It’s early days yet, but certainly technically, removing a prostate after focal therapy is easier than removing a prostate after failed radiotherapy. It certainly is more scarred around the treated area, though. Does that mean men shouldn’t have focal therapy?

I would argue not because we’re giving radiotherapy to hundreds of thousands of men. It’s an accepted treatment modality, and if it does fail, it’s tough surgery afterwards. That is, unfortunately, the nature of the beast. When the first treatment fails, secondary treatments are always going to be a little bit more difficult, if not a lot more difficult.

It is difficult to perform that second surgery or men will have more side effects after their surgery?

Dr. Ahmed: The concern is both. If it’s more difficult to perform, then are they likely to suffer more side effects? And, as a result of the surgery being difficult, are we going to get more positive margins? Are they going to fail more often?

These are men whose tumors are going to be very aggressive by nature because, as I said, they resisted extremes of temperature, sometimes twice, and there are still a few cells. So they’re going to be pretty aggressive. The failure rates might be higher in that group, just because of the focal therapy paradigm. Just like radiotherapy, when you get radio-resistant cancers they are generally more aggressive and nastier cancers just by natural selection, if you like.

Do you have any advice for men who are considering focal therapy?

Dr. Ahmed: It’s very important when you are first diagnosed with prostate cancer not to rush into treatment. It’s important to do as much reading as you can and have consultations with urologists and radiation oncologists. If you haven’t been told about focal therapy, ask whether you’re suitable. You might get an answer that says, “Well, it’s not proven.” But if you are keen to explore it, you should definitely have a consultation with somebody who does focal therapy so that they can tell you first whether you are suitable, and secondly, what the outcomes might be in your case. I think every good focal therapist will share the uncertainties, as well as the certainties, around the treatment that they give.

If they’re not sharing those uncertainties, then see somebody else. It’s also very important that they quote their own data. That data, ideally, should be published in the public domain because that is a sign, first of all, that you’re being told the right outcomes for that surgeon or physician. Also, it’s a sign that physician takes their trade seriously and is constantly looking to see how they can improve, as well as sharing their data with their peers.

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Focal Therapy

In April, we’re talking about focal therapies.

Dr. Snuffy Myers comments:

“Interest in focal therapy is fueled by the promise of cancer control with fewer side effects than are seen after radiation or radical prostatectomy. From the patient perspective, this is certainly an attractive option. As a result, we have seen the development of an increasing list of approaches to focal therapy.

There are a number of issues that make critical evaluation of the various focal therapies problematic. First, with the exception of a recent trial that involved laser, randomized clinical trials are absent. There is even a controversy about what is the best control group. The laser trial just mentioned used an active surveillance control group. The second approach would be to randomize against surgery or radiation therapy. The major problem is that such trials have proved nearly impossible to run because of poor accrual. For this reason, I suspect that focal therapies are most likely to find a clinical niche as an alternative or add-on to active surveillance.

Another issue is that we lack trials that randomize between two different focal therapies, so it is difficult to know what approach to recommend for a given patient.

For example, cryosurgery and high intensity focused ultrasound (HIFU) have both been around for many years and have never been directly compared in a clinical trial. In developing focal therapies, it is currently common practice to treat a group of patients with a new technology and then follow those patients over time. Results are reported after 1, 5, and 10 year follow-ups and comparisons made to historical results with radiation or radical prostatectomy.

However, we have long known that such comparisons with historical data are often unreliable. As mentioned above, a better, more time efficient approach would be to test focal therapies as an alternate or add on to active surveillance rather than as an alternate to radical prostatectomy or radiation.”

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Join A Clinical Trial For Biochemically Recurrent Prostate Cancer

Dr. Rahul Aggarwal is an Associate Clinical Professor of Medicine in the University of California, San Francisco Genitourinary Oncology and Developmental Therapeutics programs. He’s keenly interested in developing novel therapeutics and imaging strategies for men with advanced prostate cancer.

Dr. Aggarwal is a Co-Investigator in the ongoing Prostate Cancer Foundation’s Stand Up To Cancer-funded West Coast Dream Team prostate cancer consortium.

Prostatepedia spoke with him about his clinical trial on hormonal annihilation in men with high-risk biochemically recurrent prostate cancer.

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What is the thinking behind your clinical trial on hormonal annihilation in men with high-risk biochemically recurrent prostate cancer?

Dr. Aggarwal: This trial is for patients with prostate cancer who previously had what we call a radical prostatectomy, or the prostate was removed, as their primary treatment and then subsequently had evidence of cancer recurrence as indicated by a rising PSA. We’re specifically looking at patients with a PSA that is rising quickly with a PSA doubling time of nine months or less.

We know that this group of patients is at risk for subsequent development of metastases as well as at risk for prostate cancer-related mortality. One standard treatment approach is to use intermittent hormone therapy, which can suppress the cancer for a period of time. Inevitably, though, the cancer becomes hormone or castration-resistant.

Once that happens, patients have fewer treatment options remaining and a shorter prognosis.

The main goal of the study is to use some of the more potent hormonal therapies that have been developed, including Zytiga (abiraterone) and Erleada (apalutamide). and apply them to this situation to see if we can durably suppress the patients’ prostate cancer in a finite period of treatment. Rather than treating indefinitely, we treat everyone on the study for 12 months, and then we stop and let their testosterone levels recover and any side effects related to hormone therapy stop or lessen. Hopefully, we can see long-term control of patients’ PSA levels or maybe for some prevent the need for future treatment.

In this way you would also lessen some of the side effects associated with these treatments?

Dr. Aggarwal: Exactly. Then the total duration, or percent time, spent on hormone therapy would be shorter. Even though we’re giving more potent hormone therapy, this would actually translate into less overall treatment and less medical burden from a side effect perspective. Some of the other studies that have come out using medicines like Zytiga (abiraterone) and Erleada (apalutamide) in the hormone sensitive or castration resistant settings do seem to suggest there is a benefit to giving these medicines earlier in the treatment course. I think it fits with what we’re seeing in terms of the general trends in the use of these medicines and the management of prostate cancer.

What can a patient expect to happen step by step if he ends up participating?

Dr. Aggarwal: The treatment phase of the study consists of monthly visits for a year in which patients are getting hormone injections. Then it is a randomized study, so in the standard of care arm men would be getting the hormone injections alone once a month for a year. Then there are two experimental, or investigational, arms with added hormonal therapy. One arm has added Erleada (apalutamide). The third arm adds Erleada (apalutimide) plus Zytiga (abiraterone).

Patients have a two in three chance of being on one of the added hormonal treatment arms.

This is an open label trial, meaning there is no placebo. Everyone will get active treatment, so there’s no risk that their PSA levels won’t go down. Every patient responds initially to hormone therapy, or nearly everyone. We see patients monthly for hormone treatments. We evaluate them for side effects. At four or five time points throughout the study, we have patients fill out questionnaires regarding their symptoms. We do want to understand from a patient perspective what quality of life and symptoms are like during the course of treatment.

After one year of treatment, assuming the PSA is not rising, patients will then enter a follow-up phase which we try to make easy. We check patients’ PSA and testosterone levels once a month, but we don’t require any mandated in-person visits to allow more flexibility for those who live far away from the study center where they were treated.

At the time that the PSA rises to above 0.2, that’s the cut off for what we call PSA progression, which is the primary endpoint of the study. After that treatment is per the discretion of the patient and treating doctor. We still follow patients long term for metastases free and overall survival. The treatment options at that point are completely up to whatever is decided upon between the patient and his doctor. It’s flexible on the backend too if his PSA were to rise.

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