Rick Bangs, MBA, PMP, is the bladder cancer advocate on the genitourinary committee of SWOG Cancer Research Network (originally known as South West Oncology Group). He serves as chair of the SWOG patient advocate committee and is on the SWOG executive advisory committee. He lives in Rochester Hills, Michigan. Rick has 30 years of experience in information technology and marketing and is advising on the redesign of ClinicalTrials.gov. He is co-chair of the NCI Patient Advocate Steering Committee and serves on the NCI Cancer Care Delivery Research Steering Committee and Council of Research Advocates. Rick actively supports the Bladder Cancer Advocacy Network and Movember. He previously served on the NCI Genitourinary (GU) Steering Committee. He is a bladder and prostate cancer survivor.
Prostatepedia spoke with him about clinical trials for prostate cancer.
How did you get involved with patient advocacy in the first place?
Rick: When I was first diagnosed with bladder cancer, I sat outside the clinic, filling out forms for some clinical studies on quality of life, and I came to the decision that, regardless, some good was going to come out of my cancer.
I found out that I had prostate cancer after my surgery for Stage II (muscle-invasive) bladder cancer because, if you’re a man, when they remove your bladder, they also remove your prostate.
Three years after my surgery, I went to an advocacy event held by the Bladder Cancer Advocacy Network (BCAN). At the time, they met in two major cities a year, and Cleveland happened to be one of the cities that year, which was a four-hour drive for me. I went and met the president and co-founder of BCAN. I gave her a copy of the presentation I was giving the next day at the University of Michigan bladder cancer support group. We chatted and I offered her any help.
About six weeks later, she asked me to respond to an interview by ABC News about the disparities in cancer funding. That went pretty well, so she reached out to me about a month later and asked if I would replace her as the SWOG bladder cancer patient advocate. She said she couldn’t do everything that was being asked of her. I accepted, and that created a series of dominoes that led us to where we are.
What is it about patient advocacy that keeps you interested? What is it that keeps you coming back?
Rick: Being in the room where it happens, where change happens, and having the opportunity to work with really cool people on really cool projects to make a difference is what keeps me coming back. I enjoy doing that both directly in the spaces that I work in, which tend to be bladder and prostate cancer for obvious reasons, but also with my counterparts in the leadership roles that I have.
In bladder cancer, we’ve been on what some bladder cancer researchers once described as a “shallow plateau” for nearly a generation from a treatment point of view. That’s been changing in the last few years, but it’s been true for so long. For me, it’s raising that shallow plateau and being part of the process.
Would you say that what it means to be a patient advocate is changing?
Rick: Yes, particularly in research advocacy, a subset of this big, broad basket of things that patient advocates do. It’s amazing to see how our work is maturing.
There are things that I can do today to articulate with some specificity the work that a patient advocate does in cancer clinical trials. I can say: here’s the lifecycle, here’s what I can do at this stage, here’s what I can do at this next stage, here’s where you should involve me, and here are some other things that wrap around that from an organizational point of view. I can articulate those.
I can point to processes and expectations that didn’t exist two years ago and consensus around them. I can point to training across the five stages of the clinical trial – training on how to optimize the engagement of patient advocates and maximize the value that we bring to the party. I’m not talking about training just for patient advocates, but for patient advocates, principal investigators, leadership, and other members of a study team. That was a huge hole that we chose to fill at SWOG.
We did an environmental scan and found absolutely nothing; there was no training on engaging advocates in creating and running clinical trials. We had training for patient advocates on what cancer is, what trials are, and how to review a study concept. But we didn’t have any training for teams on how to more broadly engage patient advocates in the specifics of the activities that they work on.
What does SWOG do, and what is SWOG’s mission?
Rick: SWOG is this amazing team of exceptionally talented people who work in one of six networks in the U.S. and Canada that make up the National Cancer Institute’s National Clinical Trials Network, or NCTN. The NCTN was created by the NCI in the 1950s to test chemotherapies, which were new at the time, and it is the oldest and largest cancer clinical trials network in the country.
The whole reason that SWOG and the NCTN exists is to design, deliver, and share the results of clinical trials that will change the standard of care for patients, their families, caregivers, and partners. They’re funded by the NCI, which also provides critical support and services to the NCTN, like a Central Institutional Review Board.
That’s the general answer about SWOG and what they do, but it’s important to think about the results that SWOG has achieved. Since it was founded in 1956, SWOG research has led to the approval of 14 cancer drugs. We have also changed the standard of care over 100 times.
One of our biostatisticians did an analysis—and it’s a very conservative analysis—of how many years of human life we have saved. If somebody before a trial lived for 10 months, and now they live for 12, and if you multiply those two months times the number of people who have the disease, times the number of years since we changed the standard of care, the answer is: 3 million years of human life. That’s at least how much time we’ve saved for patients to be with their families and do things that are important to them.
When you think about the opportunity to work on things that are that important, it’s incredibly rewarding.
What kinds of trials does SWOG run?
Rick: We’re typically playing in the Phase II and Phase III space, although we also do some work in the very early Phase I (first in human) space.
We focus on trials that are going to change people’s lives in a significant way. That includes treatments and therapies but also prevention and survivorship. We don’t shy away from those topics in our scope of the work. We do research that the pharmaceutical industry itself will not do.
We work, for example, on dose reductions. You can imagine that a company has little incentive to get patients to take less of the drug they produce.
We work on alternate sequencing; this treatment, followed by this treatment, followed by this. We might look at how we ended up with a particular sequence and whether there is a better way to do the sequence.
We work on drug combinations. Individual pharmaceutical companies may have combination drugs, and they may have partners, but we look at combinations more broadly and create some synergy between drug combinations that pharma would not have considered.
We typically take on the complex and difficult. SWOG has more than 1,000 member institutions, and some are larger academic institutions, but we also have many hospitals and clinics in rural and suburban communities. The group that works to address the rural setting also makes sure we’re accounting for and addressing disparities in healthcare. We also do some work with cheaper effective drugs that may not currently get attention or investment from pharmaceutical firms.
In the bladder cancer space, we have a shortage of an immunotherapy drug that we’ve been using since the late 1980s. We were on the cutting edge back then, which for bladder cancer is like an oxymoron. We began to use Bacillus Calmette-Guerin, which is related to tuberculosis, and through testing in the late 1980s at SWOG, it was confirmed to be effective for many patients. It’s instilled in the bladder through a catheter. It’s a biologic, so there are different strains of BCG, it’s not a single drug, and it is difficult to manufacture. We have been using it for years, but now we’re down to one strain in the United States that Merck makes, and they can’t keep up with demand globally. We’re experiencing our third shortage in seven years.
SWOG is doing a study because, believe it or not, we really don’t understand how this 30-year-old treatment works, and we knew that there had been and would likely continue to be shortages, so we wanted to take care of both. We wanted to be in a position where we could address the shortages, but we also knew that there was potential to understand the mechanism of action of BCG and also potentially get better results with sequencing.
Research underlying the SWOG S1602 PRIME trial indicates, for example, that if people had a specific tuberculosis vaccination, and you waited a certain amount of time before BCG was installed in the bladder, that they got a better response than with just the installation in the bladder alone. This is because the immune system was primed through the vaccination and built up some immunity before installing BCG in the bladder.
We’re doing a trial testing a new strain of BCG with and without vaccination. I can’t imagine pharma funding a trial like this. It’s a low-profit margin drug, and people have walked away from it.
Yes, it could only come from an organization like SWOG. Pharma wouldn’t necessarily invest in, right?
Rick: Right, because they’re going after the hot, profitable immunotherapies. They’re not after this 30-year-old, low-profit treatment. That’s not where they’ll recoup their investment.
SWOG plays an important societal role!
Rick: Yes. As Americans, we don’t appreciate the return on the investment that we get from the NCI and these clinical trials. NCI pays for itself many times over. Most Americans don’t even know that the research is happening, let alone that it’s that beneficial.
Right, well, this kind of information rarely makes it to mainstream news, unless a sensational clinical trial either fails or is wildly successful.
Let’s say patients reading this understand the role that SWOG and other NCTN clinical trials play in the development of new drugs for prostate cancer. But why should they consider joining a trial? What’s in it for the individual man?
Rick: There are several reasons. First, anybody who’s diagnosed with any cancer will find that they, too, are on a shallow plateau in terms of treatment options no matter what their diagnosis, though exactly how shallow varies by the cancer. The treatments are insufficient, have unpleasant side effects, and never work fast enough. If we want to advance the science, and if we’re going to change these insufficient treatments, we’ve got to have clinical trials.
Second, no single clinical trial for a treatment ever studies a single question; we’re always doing other studies at the same time within the clinical trial. It’s like three, four or more studies for the price of one. We do the trial on the treatment, but we also learn the mechanism of how it and the cancer work, and we build up the knowledge that we need for the next set of trials. It pays off not just in terms of one clinical trial but a series of them.
Third, there are studies that demonstrate that the care that a patient gets in a clinical trial is great. Physicians who put patients on trials are very attentive and careful in their execution, going above and beyond the standard.
Fourth, giving back is another great reason for patients to join.
Last, but certainly not least, you are often given an opportunity to participate in a treatment or an intervention that may improve your cancer journey. That isn’t always the case, and there’s never a guarantee, which is why we do a clinical trial, but we know that clinical trials work about half the time. Some people clearly benefit from participating.
If a man understands that a clinical trial may be of benefit both to him and to society, should he start looking for a trial when his cancer has advanced beyond a certain level, or should he start looking for one when he’s first diagnosed?
Rick: I would suggest that a man check on a clinical trial no matter what his diagnosis, and, frankly, no matter what his disease.
There are clinical trials out there that span the entire lifecycle of every disease. People are doing work on prevention, early-stage disease, and late-stage disease. People are also doing work on caregiving. Partners, spouses, family, and friends are tightly integrated into the cancer journey, and there’s a place for them in clinical trials too. I would suggest that people ask about clinical trials no matter their diagnosis.
How would you suggest they go about finding a trial? Should they talk to their doctor, search online, or contact patient advocacy groups?
Rick: It’s always appropriate to start with a physician. The challenge is going to be the geographic dispersion of clinical trials. We know that most of them are centered in larger academic institutions and larger cities.
At SWOG and our counterparts, we have a community base that supports us, that ensures we’re getting out there. But for many patients, their physician may not know about a clinical trial.
Where should you go from there? You can search ClinicalTrials.gov, which I’ve worked on. You can search Cancer.gov, which includes only trials that are funded by or conducted at NCI sites. You can start with those and make a list, and then you can talk to the physician about narrowing that list down. Advocacy groups can be a great mechanism. Many of them are armed with people who are like me but even more focused on the specifics of the clinical trials and the disease settings. They can be very helpful. They know how to navigate online searches, but they also know how to work through the complex information about qualifying. If you’ve found a trial, you can use ClinicalTrials.gov to find the principal investigator, and you can ask them for further information and whether you qualify. Believe me, they are happy to help. Social networking is becoming a mechanism for people to connect, and particularly for folks with rare diseases or rare forms of common diseases. Facebook groups and web forums are good possibilities. Don’t be afraid to ask for help. If you talk to the physician and the physician says no, reach out to an advocacy group, or try to find something on ClinicalTrials.gov, or go out to a web forum or a Facebook page and ask about possibilities. NCI has a Contact Center that is based in Seattle. Don’t be shy about calling 1-800-4-CANCER.
What kinds of information do they provide at the call center? Can a patient, say, call up, explain their situation, and ask for a personalized list of trials available?
Rick: Yes! The NCI Contact Center helps connect a patient with a trial – but they never push a trial. These are neutral, well-trained counselors. They will go the extra mile. I don’t know what kind of success rate they have, but I know they get a large number of calls. But most people don’t even know to make the call. Contact Center staff also can chat online or answer questions by email.
Are there any considerations patients should keep in mind as they look through these trials?
Rick: The first thing to remember is that we do trials because we don’t have the answer. If you start searching for a trial, and you find something, you shouldn’t automatically assume that it is going to be successful. You have to come at it from the perspective that it may or may not benefit you personally.
Geography and institutions matter. If you ask your doctor, and the doctor says they don’t know of any clinical trials, that does not mean there aren’t any at other institutions or in other places. I would not take no as a definitive answer from a single physician, particularly in a more rural setting.
Oftentimes there are trials that require maybe an initial visit, or an initial series of visits, and then follow-up can be done remotely, correct?
Rick: Yes, though that tends to be a little tricky. It isn’t always possible. We keep trying to move in that direction. Patient advocates emphasize that as a possibility. It gets a little tricky because there are quality and recordkeeping considerations.
Convenience for the patient is certainly first and foremost, but typically specimen extractions can be complicated, even if it’s blood, urine, or tissue, and activity may need to happen around and to that sample and within a certain time. There are many complexities around that, but certainly that can be possible.
I’ve heard that it’s very difficult to find and recruit patients for trials, and that many trials don’t end up fully accruing. Is that true? Why do you think that is?
Rick: Historically, a number of trials have had to close because there weren’t enough patients. This is not current data, but some years back, about a quarter of trials had to close for insufficient recruitment.
We’re doing much better now, but why was that the case? Some trials were not as patient-centric as they might have been, and could have been better designed, asking more interesting, more potentially significant questions. Trials were mostly in large cities and access was an obstacle. We also haven’t always had exciting treatments to offer. We have more exciting things happening today. Immunotherapy is one example that’s more exciting today. So trials are much better today, though we still have challenges.
Why do we still have problems recruiting patients? First, patients are not always offered a clinical trial, in part because clinical trials are not everywhere. It’s not like I can just go to my primary care, emergency room, or my local clinic and say, “I’m here for the clinical trial.” That doesn’t happen.
There are logistical and access challenges. Patients are not always asked, and when they are, they are concerned about placebos. But we don’t do clinical trials where patients get nothing instead of something that works that they would normally receive. They’re going to get something, or they’re going to get the alternative. We’re not going to take anything away from you. That never happens, but people think it does.
There’s a misconception that clinical trials are only for people who are desperate for hope, when nothing else has succeeded. That is not the case. That keeps people from asking and participating. Trials are available across the cancer journey.
People generally have poor awareness of clinical trials, and many don’t understand how medicine works. But they should know that we have decided how and when to use every drug over many decades thanks to clinical trials. We don’t just say, “Here’s a drug that works in the lab. We know it works with a mouse, so here you go, patient.” We don’t do it that way.
Do you have any particular prostate cancer clinical trials you’d like to highlight?
Rick: I’m in the genitourinary committee, so I know a little about what’s going in the prostate portfolio. There’s a trial that we’re doing that nobody else would do. We’re asking if someone who is initially diagnosed with metastatic prostate cancer should receive treatment for their prostate. By metastatic, we mean the cancer is in the prostate and has spread beyond it.
We have similar questions in some of the other cancers. The general school of thought is that unless you respond to treatment, whether it’s chemotherapy or radiation in this particular context, we’re going to give you chemotherapy or radiation, but we’re not going to give you any other treatment to either surgically remove or radiate your prostate. That’s the standard, but there’s no good data underlying that.
We’re doing a randomized trial, so the computer decides which treatment you get. One group of metastatic patients will get some kind of systemic therapy, whether it’s chemotherapy, radiation, or another treatment. The other group will have the surgery or the radiation in addition to the systemic treatment.
How big is the metastatic trial?
Rick: It’s a large Phase III trial with more than 800 patients.
This trial demonstrates SWOG’s willingness to research these interesting, needy kinds of questions that nobody else would take on.
SWOG has other counterparts, so this is not just a characteristic of SWOG. This is what the NCI-funded NCTN network groups do.
Is there anything else that patients should know about clinical trials?
Rick: Patients should ask. That’s the big thing patients should do: ask questions, and ask for clinical trials. If there is a clinical trial that you think you qualify for, you should consider it, and ask questions about it. You don’t have to participate, but ask and consider. You owe it to yourself to do that. And if not, you owe it to those who follow you. It’s meaningful work. It may help you, but you shouldn’t just do it because you think it’s going to help you—we don’t know if it will. There is no guarantee, but: ask and consider.
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.
Dr. Edward Schaeffer is the chair of the departments of Urology at Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital.
Prostatepedia spoke with him about focal therapy for prostate cancer.
Why did you become a doctor?
Dr. Schaeffer: I’ve always been fascinated with how things work. My fascination dates back to when I was a child who loved to understand the mechanisms that made an alarm clock work. Over time, that interest in the mechanical nature of things evolved to an interest in the complexities of animals and living things. From there, I got intrigued by not just normal anatomy and physiology, but also by understanding how and why things break down. Restoring things to normal is one appealing part of medicine.
If you can understand why things fall apart, you can understand how to fix them. That is the essence of part of medicine. The other part of medicine is humanism, the ability to help people. It’s truly such an honor to help people with their problems. I’m reminded of that privilege daily.
Have any particular patients over the years stood out in your mind? Any cases that may have changed how you view the art of medicine?
Dr. Schaeffer: I have an open style with my patients, and they can all reach me through my personal cellphone number. I give them my personal number because I view my position in their lives as a privileged one.
Patients come to me with a problem, and they really open up to me about their own health problems, their anxiety and fear, and the psychological impact that their new disease diagnosis has had on their life. Because they’ve been so open with me, I view it as part of my role as a physician to give them access to me if they need me.
I’ve developed personal and close relationships with all of my patients. I maintain objectivity, but the disease I take care of is a personal one. It’s a cancer, and there can be a lot of emotional burdens that go with it. My patients are always changing my view of my role in medicine and my role in life and family. I’ve learned so much from them.
That’s fairly unusual to provide your own cellphone number, isn’t it?
Dr. Schaeffer: It’s highly unusual! But I’ve never done anything based on what other people do. I just do what I think is right.
What is focal therapy, and where does it fit into the spectrum of treatments that are available to men with prostate cancer today?
Dr. Schaeffer: Focal therapy is one type of interventional treatment for men who have localized prostate cancer and for men who have localized prostate cancer that is contained within the particular focused area of the prostate.
Generally speaking, when patients have a low-volume, low-grade prostate cancer, the first go-to option is typically a program of surveillance because we often deem these as cancers that don’t require any active intervention. But some patients want to do something or don’t want to have treatment of their entire prostate, and so they may request that we focally ablate the suspicious or concerning area. That is a potential option.
When we do focal therapy, we always have to follow the patient and monitor not only the area we treated but also the other areas of the prostate for cancers that may crop up.
In some ways, it’s more intensive active surveillance because it’s active surveillance plus something. On the spectrum, it’s a minimalist approach, but the jury is still out as to whether it’s an effective approach. While there are many anecdotes out there where people have thought it’s been successful, it hasn’t been widely studied.
Is that one of the controversies around focal therapy?
Dr. Schaeffer: Yes, I would say so. It has not been rigorously studied with one exception. One type of focal therapy, photodynamic therapy, has been studied in a prospective clinical trial. This trial was promising: it showed that focal therapy can reduce the amount of cancer and reduce the progression of cancer.
Are the side effects fewer with focal therapy than with whole-gland therapy?
Dr. Schaeffer: That is the idea of it. That is correct.
Let’s say someone gets focal therapy and then their cancer recurs. Does the previous focal therapy impact or impede their ability to get another primary therapy like radical prostatectomy or radiation?
Dr. Schaeffer: It makes it more potentially challenging to do what we would then call definitive secondary or salvage treatment, but that’s not true for every patient all the time. When somebody has prostate cancer in one area of the prostate and undergoes focal therapy, they’re monitored for two things.
One is recurrence or regrowth of the cancer locally. Second is the development of additional cancer in another area of the prostate. Individuals who have had focal therapy may require additional treatment for one of two reasons.
One reason may be that the area where the cancer was before was not effectively treated the first time. That would be disease persistence. Then the other reason may be that perhaps a cancer developed in another region of the prostate. We know that prostate cancer is a multi-focal disease, so it certainly is possible that a cancer could occur somewhere else. That is why people who have had focal therapy can’t give up monitoring their cancer over time.
Any other controversies over the role of focal therapy?
Dr. Schaeffer: The main controversy in terms of focal therapy has to do with the fact that many consider focal therapy to be a treatment, that if you can detect the cancer on MRI, for example, you could focally treat the MR-visible area. There is good research from UCLA and other groups that shows that the volume of the cancer that was originally noted on MRI underestimates the true volume of the cancer by two or three times in some cases.
So, what should you treat? Should you treat only the MRI-visible area, or should you treat the MRI-visible area plus a boundary of prostate around it because there’s this possibility that cancer may extend beyond the MRI visibility? That’s a big controversial area because the more broadly you expand your focal treatment area, the more you increase the possibility of having side effects from more extensive treatment.
Do you have any advice for men who are considering focal therapy?
Dr. Schaeffer: For all individuals with a new diagnosis of prostate cancer, they should really seek the advice of an expert. Somebody who’s well-versed in all treatment options for prostate cancer would be very helpful.
I don’t perform focal therapy myself, but I know experts who do. If I believe someone’s a good candidate for it, or if I think that someone’s not a good candidate for focal therapy, but they’re still interested, I’ll refer them to an expert so that my patients can get their advice. I think it’s important that patients seek advice from an expert in the management of prostate cancer who can help them understand the full implications of the treatment options.
Would you encourage most patients to seek a second opinion?
Dr. Schaeffer: I do, unless their diagnosis was at an NCI-designated cancer center or hospital in similar standing. If they’re at a center of excellence already, they don’t have to go to a second one unless you’re uncomfortable with your team. I think that the idea of seeking out somebody with expertise in that particular disease area is very important to get the best advice possible.
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.
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.
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.
Dr. Hu: If you look at breast cancer surgery about 40 years ago, for instance, some of the trials were done to demonstrate that a lumpectomy or a partial mastectomy in many cases was as good as removing the breast entirely. In prostate cancer, focal therapy or partial gland ablation is referred to often as the male lumpectomy.
The challenge for why there hasn’t been a partial gland approach with prostate cancer is the timeline of knowing differences in outcomes. If you took a whole gland versus a partial gland approach, you’re not going to see it as quickly as you might in breast cancer, where metastasis or death can occur in a shorter time. In prostate cancer, 95 percent of men who are diagnosed are still alive 10 years after their diagnosis.
In about 75 percent of men who are diagnosed, prostate cancer is multifocal, so even if on a biopsy you find it in one area, it’s not uncommon that when prostate is removed surgically, the pathologist detects prostate cancer in multiple areas. That’s also been a barrier to the use of partial gland treatments in prostate cancer, and multifocality is less common in breast cancer.
When you’re treated for prostate cancer, the blood test biomarker to determine whether you’re free of cancer is the prostate-specific androgen (PSA). In contrast to other cancers, when you’re treated for localized disease for instance, you don’t do CAT scans or X-rays to see if something has grown back or spread because the PSA is going to become detectable before there’s any radiographic signs of a recurrence. Therefore, if you only treat part of the prostate, the part that’s untreated, the normal prostate is going to continue to produce PSA. Therefore, the PSA is not going to be a meaningful marker of cancer recurrence with partial gland ablation. There are many unknowns in terms of how we should follow these patients who have partial gland ablation approaches.
What has driven the greater interest or the increased realization of partial gland ablations? MRIs are done commonly in the United States when men have an elevated PSA as a biomarker or as a predictive test beyond an elevated PSA of what the biopsy may show. This may help them forego a biopsy, but MRI’s increased sensitivity or accuracy for finding significant cancers is about 70-80%.
Fusion-guided platforms take the MRI and fuse them to the ultrasound, which allows us to better pinpoint where the suspicious area is within the prostate. These fusion-guided platforms have enabled a more accurate diagnosis within the prostate. This has led to the application of these MRI ultrasound fusion platforms to deliver energy to kill cancer cells that have been confirmed in those areas. In other countries around the world, there has been availability of one of the partial gland approaches, high-intensity focused ultrasound (HIFU).
Before 2015, when the FDA approved HIFU for treating prostate cancer in this country, it was pretty common for men who were seeking partial gland treatments to fly overseas and pay out-of-pocket for these treatments.
We know that HIFU kills prostate tissue, but we don’t know what the outcomes are for prostate cancer, and therefore, the FDA has not given a prostate cancer indication. You can’t market it as treating prostate cancer, and because of the absence of comparative data to other treatments, Centers for Medicare & Medicaid Services (CMS) will not reimburse the full amount for prostate cancer treatment currently.
Other insurances follow the lead of CMS. It’s an interesting time. There is a need for comparative effectiveness research for clinical trials that compare this new treatment option of partial gland ablation to established methods of surgery, radiation, or active surveillance.
What can patients expect to happen in the trial?
Dr. Hu: In our trial, you have an MRI and a biopsy within 6 to 12 months after you get partial prostate gland ablation. There may be a tendency for people to get treated and never come back, assuming that the treatment was successful. This would almost be like receiving a placebo and not wanting to receive bad news if cancer returns.
Typically, a clinical trial means that we’re offering a treatment to a patient. We don’t really know the long-term outcomes. Therefore, there is a defined follow-up. Participants agree to get treated so that we can study this and clear up some of the uncertainty for others in the future, and so that we can detect a cancer recurrence earlier with structured follow-up. Data and outcomes are tracked as they occur, or prospectively to ensure complete collection of outcomes. We want a control group in which the patients get standard treatment and we want an experimental or an intervention group who receives the new or novel treatment. This balances differences in characteristics such as age, race, other medical issues such as diabetes, cancer characteristics, etc.
The challenge with trials in prostate cancer is that few men would agree to having their fate based on randomization. If we said to your average American man with prostate cancer that we’ll flip a coin, and if it’s heads, you’ll receive partial gland ablation, and if it’s tails, you’ll get surgery, they wouldn’t go for it.
This is reinforced by 11 randomized trials in localized prostate cancer that have failed to recruit. In this case, its also a bit of comparing apples to oranges in the sense you’re comparing treating part versus treating the entire prostate. Therefore, the side effect profiles are different in terms of incontinence, erectile dysfunction, and so forth.
It’s a space that needs more studies because there are many men who are interested in this technique.
One of the unfortunate aspects with men travelling overseas for HIFU is that we don’t know what they’re getting. We know of instances in the United States where practitioners are marketing a laser approach to prostate cancer, and men are paying $25,000 out-of-pocket, but there are too many unknowns.
Another example is laser treatments of prostate cancer which are advertised online or on billboards. These need to be studied thoroughly. Unfortunately, the out-of-pocket nature of non-coverage by insurance distorts incentives with out-of-pocket payments for new technologies that are unproven and may not be studied thoroughly in that fee-for-service environment.
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.
“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.”
Dr. Daniel James George is Professor of Medicine and Professor in Surgery at Duke University.
Prostatepedia spoke with him recently about biochemically recurrent prostate cancer.
Have you had any patients whose cases have changed either how you view your own role as a doctor or how you view the art of medicine?
Dr. Daniel George: As we evolve new therapies and indications for treatment, it’s really interesting how that affects our relationships with patients. As an oncologist, my relationships with patients have become more longitudinal. What I mean by that is: people are living longer than ever. I’m beginning to recognize my treatments in the context of not just the short-term endpoint of how to control my patient’s disease in the next few months but in terms of the ramifications for his life and long-term survival. What does it mean in terms of his functional well-being, not simply now, but in a year from now or five to ten years from now?
In many ways, it comforts patients to hear the perspective, that I see them as a long-term survivor, and that I’m thinking about the implications of our treatments in a long-term perspective. That helps the patient invest in his own life and well-being for the long-term, whether that be diet, exercise, sleep, or all these other behavioral interventions that can really impact their quality of life.
You’re basically saying that prostate cancer is becoming more of a chronic disease.
Dr. George: It has been for some patients, and we’re beginning to recognize it more and more for all patients.
We used to think of short-term goals for some of our most advanced cases of prostate cancer—just in terms of disease control or palliation and not worry about the long-term implications of treatment. While on the other end of the spectrum we would have cases where we don’t have to treat the disease at all or maybe treat it minimally in others. Now I’m recognizing prostate cancer as a chronic disease for everybody, and so everybody needs to think of the long-term implications of treatments.
Likewise, we need to think of the implications of our sequential therapies and their cumulative side effects.
Can you define M0 prostate cancer, or biochemically recurrent prostate cancer, for patients?
Dr. George: This is probably confusing because of its name. We refer to prostate cancer in terms of stage. Stage refers to the extent of the disease. The Gleason Score or grade refers to how it looks under the microscope, its aggressiveness. But stage refers to the progression of this disease. Do they have bone metastases? Do they have distant lymph node metastases or other sites of disease? Or is it localized?
We usually use three categories: the T stage, which is the localized tumor, the N stage, which is the lymph node status, and then the M stage, which is the presence of metastases that are distant from the prostate. M0 refers to patients who have no distant metastasis. Think of M0 in terms of patients who are newly diagnosed with prostate cancer.
Recurrent prostate cancer patients are those who’ve had local therapy, surgery, or radiation, and who now have evidence of disease recurrence by PSA. After these treatments, we know that your PSA should be 0 or very low, and it should stay low. If your PSA rises and continues to rise, that’s an indication of disease recurrence. Yet, in many cases, they’re what we call M0 because, when we stage the patient with a bone scan or a CT scan, we can’t see any evidence of cancer. Many of those patients have what we might otherwise refer to as microscopic metastatic disease, disease that’s just below the level of detection. Some of them could have local recurrence or recurrence just within the pelvis and regional nodes that’s not distant. We now know from recent studies that the majority of those patients are going to relapse with distant metastatic disease. In other words, they have distant metastatic disease, but it’s just below the level of detection.
So, this is a bit of a misnomer because we’re treating them with systemic whole-body treatment therapy now because we recognize the risk of distant metastatic disease for the majority of these patients. We’re beginning to use newer imagining techniques, such as PET scans, that could be more sensitive at picking up this microscopic metastatic disease. That shouldn’t deter us from applying the current data to that patient population.
I think of M0 prostate cancer as being low-volume castrate resistant prostate cancer. When we think of it that way, it makes sense that the drugs we’re using work and work even better in that low-volume population. We should use them because M0 is just an early continuation of that metastatic process.
What are these systemic approaches that patients are likely to receive? What are the implications down the line in terms of side effects, and in terms of the longer longitudinal quality of life issues you mentioned earlier?
Dr. George: This is an important aspect of the care for these patients because we have two studies—and a third will soon be reported—that demonstrate a clinical benefit from using what we have broadly termed secondary hormonal therapies, therapies that we add to primary androgen deprivation (ADT) or testosterone suppression.
Patients for whom testosterone suppression has failed can respond to another hormonal intervention later. These are drugs that target the androgen receptor, the protein that testosterone binds to, and inhibits it from signaling. It shuts off what seems to be the most common mechanism for resistance to testicular testosterone suppression. That is an overexpression or overabundance of this receptor, which makes prostate cancer cells sensitive to low levels of residual testosterone in the body.
Xtandi (enzalutamide) and Erleada (apalutamide), in two separate Phase III studies, have demonstrated a clinically significant benefit: a delay in the time to metastasis. The FDA has accepted this as a meaningful endpoint because of the degree of delay. It was associated with about a two-year delay in the time to metastasis in this population.
Patients who were at high risk for developing metastatic disease were in the control arm and developing metastatic disease within about a year of coming on the study for the placebo arm. For the treatment arms, with Xtandi (enzalutamide) or Erleada (apalutamide), we’re seeing a delay of about two additional years. That means three years until the time of metastasis.
The results suggest that we’ve changed the progression of this disease dramatically. In addition, both studies showed a strong trend in favor of the treatment arm for improved overall survival associated with this delay in metastasis. Even though the data may not be as complete because it takes a longer time to report, we’re seeing this correlation in metastasis-free survival, if you will.
Again, I caution the semantics here because these patients do have metastases; they just can’t be seen yet. But the delay in that radiographic appearance of metastasis is associated with an improved survival.
What’s the approach to finding smaller metastases earlier on with the newer imaging techniques? And if they are very small, do you treat them aggressively with radiation, do you continue using the systemic therapies, or do you use a combination?
Dr. George: There is a mix of presentations of patients. When we image with a novel PET-imaging tracer, we’re going to see more than one site of disease in most patients. We’re going to see multiple lymph nodes, multiple bone metastases, or maybe lymph and bone metastases.
For a subset of about 20 percent of patients, we see this disease limited to only lymph node disease or only one or two bone metastases. We refer to this as oligometastatic disease, which we have yet to biologically define. Clinically, we know that it’s associated with a longer survival.
Oligometastatic prostate cancer raises the question of whether or not these patients could be managed with therapy localized to those sites, therapy that does not necessarily expose them to further systemic therapy. We don’t have a lot of data in the castrate-resistant setting, but in the hormone-naïve setting, there are some data that suggest that there can be a delay in the time to initiating subsequent hormonal therapy by doing that.
There’s a study out of Europe, but the median effect was relatively small, just a few months. It’s not clear that this is going to be a meaningful difference for most patients, but it is something that can be discussed.
A lot of those treatment approaches can be done with minimal intervention, external radiation, ablations, or limited surgery. Those will be options. But in the majority of these patients that we do this molecular imaging for, we’re going to find evidence of more than one site of disease or multiple lesions. This suggests that they need a systemic therapy approach.
It’s reasonable to extrapolate this data because we know from the placebo arm of these studies that these patients went on to develop metastases in their bone scan or CT scan within months, 50 percent of them within a year, and many of them in just a few months of their subsequent scan. The likelihood is, if we’d done the molecular imaging at baseline on these patients,we would have seen it. Yet still, in this population, we’re seeing a treatment effect.
We see the treatment effect regardless of what level of PSA doubling time you have. In patients who have a PSA doubling time of just two or three months, we see a dramatic treatment effect. In patients who have a doubling effect of eight or ten months, we still see a dramatic treatment effect in terms of prolongation in the time to metastasis—fewer events in those cases, but still, we see that treatment effect.
The PSA doubling time is an important parameter that we’re using now, in addition to these imaging stats, to determine who we should treat with these drugs and their prognosis.
Isn’t doubling time an indication of the aggressiveness of the disease?
Dr. George: It is. We knew this earlier in disease prior to hormones. PSA doubling time was very prognostic for time to metastasis and overall survival. It’s been less studied in the castrate-resistant setting, when patients have progressed on primary hormonal therapy, but we’re still seeing it there. In fact, the results are really dramatic.
There were some abstracts at the Genitourinary Cancer Symposium (GU ASCO) around this data. There have been reports from these two Phase III studies with Xtandi (enzalutamide) and Erleada (apalutamide) that demonstrate this. We believe there is a strong correlation between a shorter PSA doubling time—a shorter time to bone metastasis—and shorter overall survival.
Just to put these studies into context, the requirements were that PSA doubling times were less than ten months. If doubling time is a year or longer, these are slow-growing cancers. Even though they’re castrate-resistant, these are patients who will live for many years with no metastasis, so it’s reasonable just to observe their disease. For the studies, the median or 50th percentile PSA doubling time was around four months. That’s really short and aggressive.
That’s why we saw that the average time to metastasis was just about a year in the control arms. It’s important to recognize where your patient is in this continuum because it guides whether we should treat him like we did on the study, or if their disease is too slow growing to justify the treatment.
What other considerations are important for patients who fall into this category?
Dr. George: The important thing for patients to know: not to worry. I know that as a physician, it’s easy to say ‘don’t worry about your rising PSA level,’ but as a patient, it is hard to ignore.
Join us to read the rest of Dr. George’s comments about 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.