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Conversations With Prostate Cancer Experts


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Ms. Merel Nissenberg: Hypofractionated Radiotherapy

IMG_3119Ms. Merel Nissenberg is the President of the National Alliance of State Prostate Cancer Coalitions, a nation-wide organization comprised of state prostate cancer coalitions dedicated to saving men’s lives and enhancing the quality of life of prostate cancer patients and their families through awareness, education, and the development of a public policy network.

She offers two views of hypofractionated radiotherapy for prostate cancer.

NASPCC supports the use of new treatments and therapies that good evidence shows help prostate cancer patients, but only those that do not have more risks than benefits as compared to conventional care. Consider radiation therapy in prostate cancer. As radiation therapists and medical oncologists consider future trends in radiation therapy for prostate cancer, there are two settings in which the idea of hypofractionated radiotherapy is being explored. It may not yet be ready for prime time.

The first setting is either the postoperative adjuvant period for prostate cancer patients with aggressive pathological features following radical prostatectomy or as salvage therapy for patients with biochemical recurrence after prostatectomy. Although there is now evidence from Phase III trials supporting the use of hypofractionation in terms of good biochemical control and favorable short-term toxicity, the role of such radiotherapy in these patients is still considered investigational due to conflicting results with long-term genitourinary late toxicity.

The second setting involves men with localized prostate cancer who are often treated with external beam radiation therapy (EBRT) as their primary treatment, with treatments given over the course of 8-9 weeks. For these types of localized prostate cancer patients, trials are now being conducted to ascertain the noninferiority of hypofractionation.

That is, can larger doses of radiation per treatment over a shorter time be just as effective as standard EBRT and with no increased toxicity?

In one such trial reported in Journal of Clinical Oncology in 2017 (V35, no. 17, 1884-1890), intermediate risk patients were randomized to either conventional radiotherapy of 78 Gy in 39 fractions over 8 weeks (598 patients) or to hypofractionated radiotherapy of 60 Gy in 20 fractions over 4 weeks (608 patients). No androgen deprivation was allowed during the trial.

The primary outcome was “biochemical-clinical failure” (BCF), defined as the first occurrence of any one of 4 outcomes: PSA failure, hormonal intervention, clinical evidence of local or distant failure, or death as a result of prostate cancer. Median follow-up was 6 years.

The five-year BCF disease-free survival was 85% in both arms of the trial, and there were no significant differences between the two arms in terms of grade 3 or worse late GU and GI toxicity. There were twelve deaths as a result of prostate cancer in the standard RT arm, and ten deaths as a result of prostate cancer in the hypofractionated arm.

The trial investigators concluded there is evidence to support the use of moderate hypofractionated RT in patients with intermediate-risk prostate cancer but not in high-risk disease.

For hypofractionated radiotherapy to be adopted as standard practice for patients with intermediate-risk disease, it must be shown to be equivalent or superior to conventional radiotherapy in terms of excessive toxicity, especially late radiation genitourinary and gastrointestinal toxicity. More studies are therefore needed, particularly because there has been conflicting evidence in terms of such toxicity.

While some reports from last year conclude that moderate hypofractionation is safe and effective for localized prostate cancer and further suggest it should be standard of care, it cannot be over-emphasized that caution is strongly urged.

Longer-term toxicities are not yet known from the increased dosage of radiation with the new modalities. NASPCC strongly supports more clinical trials and longer-term follow-up to answer the question of long-term toxicity with the use of hypofractionation.

Subscribe to read our July conversations about radiation therapy for prostate cancer.


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Patients Speak: Let’s Talk About It

Gary H spoke with Prostatepedia about prostate cancer journey and the choices he’s made along the way.

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How were you initially diagnosed with prostate cancer?

Gary H: I live in Colorado, and I get a physical every year. I didn’t know this, but my doctor started checking my PSA at 40. About five years ago, when I was 54, my doctor said my PSA went up from 2.0 to about 4.4. He said there was a small chance of cancer, but when it gets up to that number, it’s important to check it, so he recommended a biopsy. I went in there just for a physical. Next thing you know, I’m going to get a biopsy.

I found a good doc, went in, and did the biopsy. He did about 12 needles. It turned out that I had some cancer in certain parts of my prostate.

He said, “You’re a young guy. Just go take it out.” But I started researching more and more, and because my PSA wasn’t going up very fast, I started the journey looking at what to do.

Where did you go for research? Did you turn to the internet? Friends?

Gary H: Yes. I talked to people I know who knew someone who went through it. I just talked to lots of people who had a friend, brother, or relative, and I just called them. From them, I heard everything from “I had it taken out” to “active surveillance.” I was getting calls about the proton or doing brachy. I was amazed by how many different approaches there are. I got a feeling for what I needed to do, and then I talked to four or five top surgeons and in different places, like Sloan Kettering, Johns Hopkins, and MD Anderson.

You did your due diligence.

Gary H: I sure did. I did everything I could possibly do, and from what I understood, if PSA is under 10, it hasn’t spread. I had about 8, but it wasn’t going very fast. I found a fairly young fellow in Denver that I had a lot of confidence in. After speaking with about seven people who had it removed and told me what to expect, I elected to have it removed. That was a big decision.

How did you find the surgeon that you ended up going with?

Gary H: I felt that someone who had done thousands of prostatectomies was just knocking them out, going right through them and probably pretty fast. I wanted someone who hadn’t done so many but who really took his time, someone very serious about it, someone who cared maybe a little more. The surgery may take only an hour, but I wanted a meticulous person.

A friend of mine who sold healthcare products in hospitals all over spoke very highly of this one doctor in Colorado. That’s how I found my doctor. Then I had to decide between the old fashioned or robotic way. While the guys that go in there with their hands can feel what’s going on, which can be beneficial, there can be a lot more bleeding. I chose robotic because there would be less bleeding, and I’m glad I did.

Did you have any side effects after the surgery?

Gary H: Not really. Because I was young, they said I should be fine, and I really didn’t have any side effects. It took me a little longer to heal than I thought it would. I started exercising maybe before I should’ve. I should’ve waited a little bit longer.

Otherwise, everything went the way it was supposed to, and everything was great. That was a little over three years ago. I have been as athletic as ever, and I never had a problem with incontinence.

What kind of monitoring did they do after the surgery?

Gary H: About every three months, for about three years, I had my PSA checked. About five months ago, my PSA showed up as 0.02. Before that, it was 0.01, which is what they call undetectable. It’s still undetectable, but it went up to 0.06. I just had another test, and I’m waiting on the results. It’s a whole new program now.

As far as what I’ve learned, the doubling time is the big thing, and so it’s been doubling every two or three months, which is pretty quick. But the number is very low. I’m starting to ask questions again, but the speed is the concern, not so much the number.

Right: the velocity, they say.

Gary H: Right. Depending on this new test, I may have it radiated.

Is this something your doctor suggested, or is this a result of your previous research and discussions with other men?

Gary H: Probably a combination. My doctor initially told me that if it gets to 0.20, we should look at doing radiation and maybe hormone. Then, it was only 0.02, so I had a long way to go. Because of the speed of it, he advised to just have it radiated, that I didn’t need the hormone at this point. Because the doubling time is minimal but going faster, the velocity threw me a curve ball.

Have you had any imaging studies to see what’s going on, or is it so far just blood tests that you’re getting?

Gary H: No. No imaging. It’s because the number is so low. They say they wouldn’t be able to detect anything. But I plan to probably do the imaging. My one doc says it doesn’t get in your bones until it goes up to 40 or 50. A PSA of 0.03 or even 0.06 is really just starting to get going, so it’s most likely still in the bed.

For right now, you’re just in a waiting game, right?

Gary H: Yeah. I’m waiting today, actually. But I’m not concerned or worried. It’s a nonissue because of all the information. The more you know, the more comfortable you are. And it’s really out of my mind until maybe the day I’ve got to go and have blood work. Then, I feel like I’m in the electric chair for the next six to eight hours until I find out.

There’s that waiting thing, right?

Gary H: That’s right. That’s the only real negative, I suppose.

They call that PSA anxiety.

Gary H: Yeah. There you go. And now I’m not too worried. There are lots of great technologies and options. It’s just the radiation that concerns me, really. I’ve got to be in one place for two months. That’s the thing.

There are many good radiation therapists out there, so I’m sure you’ll be in good hands. It’s also good to have an action plan for what you would do next if you need to take more action, right?

Gary H: It sure is comforting that way. Now, what I went through with prostate cancer is not the same as other forms of cancers. I guess I could say I’m very fortunate to have found it when I did and to have had a doctor that was checking me all the time.

Right. You didn’t even know you were getting your PSA checked.

Gary H: I didn’t even know.

Do you have any thoughts for other men who are newly diagnosed or in a similar situation to yours?

Gary H: When you first hear about it, your initial reaction is: okay, what does that mean? Prostate cancer hasn’t really= changed my life. I still exercise. I feel great. I compete as a golfer. It’s not like all of a sudden I’ve got to go and sit in a chair, and read a book for the rest of my life.

It’s just a nuisance more than anything.

That’s if you stay on top of it. Now, of course, it could’ve been a lot worse. I had an uncle who passed away back in 1982 of prostate cancer, so it was in my family. He had waited and waited. He was supposed to have it out, but he was afraid, so he waited an extra year or two. By then, it was too late.

Do what you have to do initially, and learn as much as you can about your disease. There are lots of people to talk to and options out there.

At one point, for example, I was going to do the brachy. Once, I almost did the cryo. I was actually up at 6:00 am getting ready to go to the hospital for the cryo treatment, but I didn’t. I just didn’t feel right. I went the aggressive route and had it removed. Just do what you have to do. It’s not a painful experience, really. It’s more of a nuisance from your daily activities.

You have to step back, reevaluate, and take some time. Figure out what approach to take, and go that route.

What about reaching out to other men because it sounds like you really did? You had a lot of discussions with your friends and family. Would you recommend that other men do that as well?

Gary H: Oh, absolutely. Everybody’s different. I know people who are not very social and just rely on the internet. Others will talk to every Tom, Dick, and Harry, and that’s how I was. I did a little bit of everything. I had three close pals who had it, so I talked to them.

Everybody’s an individual and different about what approach they want to take. I have a friend who has a similar situation to mine, but he’s chosen active surveillance. He’s really staying right around that number, and it’s not going anywhere.

You do read conflicting things, for example, that PSA is not important, but it is important. If it’s on the move, you need to do something about it. So, reaching out and talking with other men is important, even just to sort through conflicting information.

People find it helpful to listen to other men’s stories.

Gary H: I like it a lot. I travel all over as a competitive golfer, and I always wanted to hook up with some organization, so while traveling, I could speak in different towns each week. I am competing. I’m out there. I’ve been through it all. I’d like to share with others.

There’s still a bit of a cultural shyness or reticence about speaking about prostate cancer. Perhaps it’s a gender thing, but a lot of men are hesitant to talk about it.

Gary H: Yeah. I’m not. I’m not at all.

Any way you can get the dialogue out there is good.

Gary H: I’m very open about it. I don’t have a problem. It’s a certain age. It’s not like an 18-year-old so much. We’re older now. Let’s talk about it.

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Health/Tech Collaborations For Prostate Cancer

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles, has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with him about collaborations between healthcare and tech industries for prostate cancer.

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Have you had any particular patients or cases that changed how you view your role as a doctor or how you practice medicine?

Dr. Paul Nguyen: Several years after treating him, I heard from a patient who recounted for me what it was like to meet with me when he had first been diagnosed with recurrent disease. He said he’d had a lot of uncertainty and anxiety about his future. He said that the way I spoke with him had changed it entirely for him. He said I had a plan for him, knew exactly what we were going to need to do, and that we were going to do it.

I didn’t do anything particularly different in that encounter than I normally do, but hearing that made me realize how patients really hang on our every word, our every facial expression, our every cadence, and the emotion that we project when we speak. This made me so aware and conscious of making sure that, at all times, in every encounter, I have that combination of being sure about what I need to do and maintaining hope and optimism in every part of our discussions.

That was a good learning cycle for me. I hadn’t thought of it that way when I was with a patient. You just don’t think that every intonation, every gesture has such a huge impact. But it does. That was a very valuable learning experience for me that has really shaped how I think about every patient encounter before I walk into the room.

What are your current research projects? Which are you most excited about?

Dr. Nguyen: I have spent my entire career using information from the medical record about patients’ health status and tumor characteristics to figure out which men should get hormone therapy and for how long. Now, I’m incredibly excited about the opportunity to unleash the power of genetic testing of tumors. This will help us understand, on a genetic and molecular level, which patients should be given hormone therapy and for exactly how long. This will be a lot more precise than the clinical information by itself. I’m working with Dr. Felix Feng and others, which has been a wonderful collaboration.

How do you see evolving technologies impacting prostate cancer research? Dr. Nguyen: Technology gives us opportunities to do the kinds of studies we never dreamed possible, which is amazing.

I’ll give you an example. Dr. Feng and I are about to take prostate cancer samples from biopsy tissues taken 25 years ago from men who had cancer, samples stored without a clear purpose in mind. I give a huge amount of credit to the people who designed these studies in the early 1990s. They had no way to analyze this tissue, but they knew that someday, this tissue would be important to humanity. There wasn’t a specific test that they were storing these samples for, but they knew some kind of technology could decode what was going on in those tumors, to study how the tumors work, and who should get which treatment.

I feel so fortunate to come along 25 years later, when we do have the technology to analyze this tissue, and research it. This is the research I’m about to do now, which would never have been possible without new technologies.

Do you see technology impacting how we design clinical trials from the get-go?

Dr. Nguyen: Absolutely, because now people are designing trials with technology. There’s a trial being led by Dr. Feng from UCSF and Dr. Dan Spratt at the University of Michigan that incorporates genetic technology.

All the patients are tested upfront with this new technology to help decide which arm the patient goes into, which is really cool. This new scientific technology is being worked into clinical trial design.

Which innovations or technologies have the biggest impact?

Dr. Nguyen: There are two kinds of impacts. One is the ability to do large-scale genomic studies for a relatively low price. That has been a game-changer because it used to be so expensive to sequence the DNA of patients, but now you can approximate that rather cheaply and then do studies on thousands of patients. This way, we can pick up very small signals, which are very valuable.

The other invaluable impact is the ability to detect very minute amounts of tumor in the blood, very tiny traces that can tell us a lot.

In the circulating tumor cell?

Dr. Nguyen: Exactly.

Do you think artificial intelligence will play a role?

Dr. Nguyen: For sure. I’ve spent most of my career working on simple, clinical data. You can see the patterns of simple data yourself by doing simple statistical analyses. But now, the patterns are much more complex. Instead of five datapoints, you might have two million datapoints per patient. So we need AI. We need sophisticated machine learning to help us discern some kind of pattern out of that huge amount of data, to help us make sense of it.

Are there any specific collaborations, other than the ones we’ve already discussed, that you think look promising?

Dr. Nguyen: We’re seeing a lot more collaborations across specialties and disciplines to get research done. So much of what we’re seeing now is team science whereas people used to do studies with their own group.

Now, if you look at a paper, it’s not just one group or one discipline. At each institution, it’s five disciplines, and then you might have ten institutions on a paper, each contributing something different because that’s just what it takes now.

Every group has its own, little special expertise that gets put together to get a big paper or a big trial done. That’s what has really exploded. We’ve all recognized that, in order to get good science done, we have to team up.

Is just it easier to collaborate with people now via email and sharing of data? Or is there something about the way cancer research has been funded that has fostered that collaboration?

Dr. Nguyen: Yes. Those factors definitely contribute. It is definitely easier to share data now with the internet. Efforts to fund team science have definitely led teams to be created that might not have been created organically before.

There’s something fundamental about the increasing use of technology in studies and trials where only certain groups have this kind of technology expertise. You might have one group that knows a lot about the technology and another group that has a large number of patients and ideas. And you have to reach outside of your little sphere in order to get these kinds of exciting studies done.

It seems like before everything was pretty much siloed: you had tech, you had healthcare, and then, within healthcare, you had prostate cancer versus pancreatic cancer versus breast cancer. But now, the walls are coming down between those silos, with things like increased genetic testing. Would you say that’s true?

Dr. Nguyen: Absolutely. For example, some of the cool studies done in prostate cancer genetics were modeled on similar research done in breast cancer genetics several years before. Breast cancer had the Oncotype study, and then prostate cancer developed the Oncotype test many years later. We’ve seen molecular subtypes of breast cancer (luminal A, luminal B, and basal), and now there’s a study led by Dr. Feng suggesting that you’ve got similar kinds of subtypes in prostate cancer. We have to be knowledgeable about other fields. You can’t just be in your own silo now.

Last week, I spoke with engineers at University of Pennsylvania who are working with microchip-based technologies and machine learning to increase liquid biopsy’s usefulness in pancreatic cancer. They said this allows them to process much more data than they could before. They hope this has potential in other cancers. I know that’s more along the lines of diagnostics than what you’re doing, but do you have any thoughts about that?

Dr. Nguyen: We are all trying to take those same kinds of approaches with the folks who do machine learning. We need them desperately now because we’ve got so much data, and we just can’t figure it out on our own.

That’s exactly where we’re all headed.

Join us to read the rest of Dr. Nguyen’s comments on collaborations between the health and tech fields for prostate cancer.


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Collaborating For Prostate Cancer

This month, Prostatepedia explores collaborations between tech and health care in the world of prostate cancer. Long gone are the days in which individual doctors and scientists operate in silos to both treat patients and conduct research.

Join us to read about collaborations between health care and tech for prostate cancer.

Large multi-institution and multidisciplinary collaborations that leverage emerging technologies to both collect data and to make sense of that data are the name of the game.

In our first two conversations, we feature two leaders in prostate cancer today—Dr. Felix Feng of the University of California, SF and Dr. Paul Nguyen of the Dana-Farber Cancer Center. Both discuss current projects that exploit emerging technologies and speculate about what the future might—they hope will—hold.

Dr. John Wilbanks of Sage Bionetworks discusses his company’s role in the National Institute of Health’s newly launched precision medicine initiative All of Us. (Some of you may remember a conversation with another Sage Bionetwork member, Dr. James Costello, in Prostatepedia’s May 2017 issue.) Dr. Wilbanks offers a unique perspective; his former role as the executive director of the Science Commons project at Creative Commons placed him at the intersection of tech, health care and patient advocacy arenas. All of Us would love men with prostate cancer to participate in the project.

Ms. Jina Ko and Dr. David Issadore of the University of Pennsylvania discuss using liquid biopsy and machine learning—or artificial intelligence—to diagnose pancreatic cancer. They argue that the technology they’ve developed should work for any cancer type, including prostate.

Dr. Matthew Galsky of the Tisch Cancer Institute discusses his efforts to incorporate telemedicine into clinical trials. As we learned in our conversations about prostate cancer clinical trials last month, the distance that you have to travel in order to participate in a clinical trial can often be a deal-breaker.

Mr. Dave Furher of Gryt Health introduces us to Stupid Cancer, an app that connects patients. Mr. Fuehrer is keen on getting more prostate cancer patients to lead in-app chat rooms. Those of you who lead support groups may be interested in participating: this is a way for you to reach men outside of your local communities, men perhaps isolated and in need of support.

In his quarterly column, Mr. Jamie Bearse of Zero discusses an astounding increase in federal funding for prostate cancer research. Zero’s tireless work on Capital Hill benefits all men. If you haven’t yet, take a look at their website to review some of the work they do and the tools they provide for men like yourself.

Finally, Gary tells us about his own prostate cancer experience and offers advice for those of you in a similar situation.

Our conversations this month underscore the tremendous changes happening in the world of prostate cancer The next five years will totally revolutionize the way we diagnose and treat prostate cancer as well as the way in which we conduct research about the disease.

These are exciting times, friends!

Join us to read our June conversations.


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Clinical Trial Eligibility + Black Men

Ms. Marie Vastola is a Clinical Research Assistant in Radiation Oncology at Dana-Farber/Brigham and Women’s Cancer Center. She works on Dana-Farber-led and international clinical trials that accrue men with multiple stages of prostate cancer. She is an author on six research articles focusing on prostate cancer and has presented her research at a national conference.

Dr. Paul Nguyen is an internationally recognized expert in prostate cancer clinical care and research. He has published over 250 original research articles and has various national leadership roles and is the Dana-Farber Cancer Center Genitourinary Clinical Center Director for Radiation Oncology, Vice-Chair for Clinical Research in the Department of Radiation Oncology, and Associate Professor at Harvard Medical School.

Prostatepedia spoke with them about how eligibility requirements for prostate cancer clinical trials may unfairly exclude African American men.

How have black men been underrepresented historically in prostate clinical trials? What are some of the prevailing theories or ideas about why that might be?

Dr. Nguyen: It’s multifactorial, and that was something that our research aimed to get at. Because of the historical experiences like the Tuskegee experiment, some African- Americans may have been more leery of engaging in clinical trials. Because trials require certain costs and extra time away from work, this can be more difficult on certain populations. Or it could be from the doctor side. Some doctors may not be as willing to engage African-American patients to enroll them on trials. There are multiple factors, so it’s hard to know exactly what is the main driver.

Ms. Vastola: We have patients come from long distances to Dana-Farber, and they do that because they know that Dana-Farber is a good place for them to get treated. Many patients, especially ones who travel long distances, either have connections in the medical field and that’s how they found out about this, or they’re highly educated and they have the resources to look into research and potential treatments themselves. These are tools that only people who are a little more privileged have.

Why did you zero in on eligibility criteria? What were you looking at?

Ms. Vastola: Actually, a patient is what started this research project. I had been screening an African-American patient for one of our open trials, and filling out the paperwork to determine if he was eligible. Most of this paperwork is related to the cancer, to make sure that patients have the type of cancer that we’re studying. But other sections of the checklist establish that the patient is otherwise healthy. We wouldn’t want to give an experimental treatment to a patient who wasn’t healthy for their sake and for the research’s integrity. He didn’t meet the criteria for one of those health checks.

One of the ways we determine that a patient is otherwise healthy is to look at their immune function, and his white blood cell count was too low. I hadn’t seen that before, and we ran his blood test again. His medical oncologist said the patient had benign ethnic neutropenia, which I had never heard of it until then. Because of that he couldn’t go on the trial that we had. It wasn’t a trial that we were running out of this hospital, but we talked to the sponsors. And as with many big trials, they don’t allow exceptions, no matter what.

He didn’t get the opportunity to be on a trial that was designed for men just like him, and that was really frustrating. Everyone involved with his treatment was frustrated with that, and so we looked into if that could be happening to other men. We also looked at creatinine. It’s well known in the medical field that black patients have a higher serum creatinine, and so you have to use a special formula that accounts for race when you’re looking at their kidney function. We looked at benign ethnic neutropenia because that’s what started it, and it was something that people seemed unaware of.

Dr. Nguyen: In a research group, the ideas usually come from the lab principal investigator (PI), and then the junior people carry it out. In this case, Marie actually came up with this idea herself because of a patient experience that she had, seeing an African-American patient not be able to get on one of our trials. It’s what led to this Journal of the American Medical Association Oncology paper, which is impressive.

That is. What did you look at?

Ms. Vastola: We wanted to know how often this happens. Was this a fluke, or does this happen to other African-American men? The best way to find out was to look at the eligibility criteria of other trials. Every trial records when people don’t meet the criteria. They don’t often record why though, so we couldn’t just look at the internal records of our trials. The website clinicaltrials.gov lists all trials available to patients in the United States and also a lot of international trials, and it usually lists the eligibility criteria. Not all the trials go into detailed criteria, but many do. We went through 401 trials that had endpoints that we thought meant that they had the potential to reach large audiences and change practice. We looked at all of them and pulled the eligibility criteria to see how many of them had this white blood cell criterion.

We expected some would have it. We did not expect that almost 50% of trials would have either of these two criteria. We were also surprised that the serum creatinine criterion was so common that a quarter of the trials have it.

People are aware of this, and they know to calculate kidney function accounting for race. A lot of trials would use serum creatinine, which is just the blood test, but then they would also say that if a patient meets formula criteria (based on race), then they’re okay, which is what we want to see. Not all trials do that, and that’s the issue. Every single lab result you look at that measures creatinine says at the bottom that if the patient is African-American, apply this formula. But over 25% of these trials weren’t including that formula.

What else did you find?

Ms. Vastola: Those were the two criteria that we looked at. We also broke it down by year, size of the trial, the phase, and toxicity of the therapy. We were glad to see that, over time, people are using the serum creatinine eligibility criteria less and less, which may mean that more people are aware of it. That’s not the case for the white blood cell criterion though.

Dr. Nguyen: We looked only at trials that have survival as an endpoint, so these are trials looking to make people live longer. We think it’s especially important that all patients have equal access to these kinds of trials. There are a few consequences of not having African-Americans on these trials. Patients who go on trials can sometimes get access to new drugs, so it’s a problem if African-American patients aren’t getting on trials. We also don’t get to learn enough about whether certain drugs perform particularly well in African-Americans, and so we don’t get to learn about the specific benefits or lack of benefit of certain agents for African-American patients. We wind up extrapolating from the larger patient pool, which probably works most of the time, but perhaps there’s something special that we can learn from having African-American patients on trials so that we could find better cures that can be tailored for African-American patients.

Ms. Vastola: Exactly. Not having access to these clinical trials hurts the individual because they don’t have access to treatment that could potentially help them. But the lack of access also hurts the whole population.

It also skews your results, so that what you’re learning about isn’t really prostate cancer in all men, just prostate cancer in a subset of men.

Ms. Vastola: Exactly.

What do you hope this will mean for clinical trial design and eligibility recruitments?

Ms. Vastola: We presented this research letter at the Prostate Cancer Symposium of the American Society for Clinical Oncology in poster form. We got a lot of feedback from academic investigators, people who devote their lives to this. Their papers define the field. They said they’d never thought of this, and that some didn’t know benign ethnic neutropenia existed. This section of the eligibility criteria—the part that defines whether a patient is healthy—is just carried over from trial to trial because it’s so standard. It’s not something people think about when they design trials because it’s so standard.

It’s textbook. We hope that, as more people understand this, they will consider it when they design their trials.

Dr. Nguyen: We were guilty of it in our own trials, and that’s how this all came about. We just used standard entry criteria copied over from previous studies. We were surprised to learn that this could disproportionally disadvantage African-American patients from being able to enroll in our trials. Given all the barriers that African-American patients face in getting on clinical trials in the first place, the last thing that we need is yet another barrier.

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Prostate Cancer, NIH + Clinical Trials

Dr. Ravi Madan (@Dr_RaviMadan), the clinical director of the National Cancer Institute’s Genitourinary Malignancies Branch, focuses on immune stimulating therapies. In particular, he’s interested in how we can combine these approaches with other therapies to improve patients’ lives.

Prostatepedia spoke with him about clinical trials for prostate cancer patients.

Why has it been difficult for doctors to enroll patients in clinical trials?

Dr. Ravi Madan: The reasons vary from case to case. Sometimes physicians don’t mention relevant trials at the right time for patients (when they’re making treatment decisions). Sometimes patients don’t want to go through the process of enrollment because of the perception that it delays their care and that delay will somehow impact their outcome. There is also personal preference. Some patients really don’t like the uncertainty of a clinical trial—uncertainty in terms of what their treatment will be if there’s a randomization or uncertainty about the outcome.

Trials should be discussed with patients when they’re making a decision to change therapies. While enrollment does take time, it’s usually only a few weeks, and for the most part, that doesn’t impact the patient’s outcomes or overall course. Ultimately, patients need to have a risks/benefits conversation with their doctor to determine if a clinical trial fits into the personal treatment strategy that they’ve developed with their doctor and their family.

Perhaps many people assume clinical trials aren’t really available until you have advanced disease, but that’s not really true is it? There are trials available at all stages along the journey.

Dr. Madan: Correct. Trials exist in all stages of the disease. The ones that often get the most notoriety, either on television or in the news, are the ones for late-stage patients. But for example, here at the National Cancer Institute (NCI), we have trials for every stage of prostate cancer, from patients who are newly diagnosed to early recurrence to non-metastatic, and then ultimately, late-stage disease.

Why would someone want to join a trial? Just to gain access to a treatment he may not otherwise have access to?

Dr. Madan: Sometimes you get access to treatments earlier than they may be available to the general public. People should understand that clinical trials often involve the standard of care they would get anyway plus an experimental agent.

There is an altruism component to a lot of this as well. It never ceases to amaze me, but when I deal with the patients here at the NCI, so many of them tell me: “If this helps me, that’s great, but I just want to help someone else later on.” It’s not like everybody has to have that reason, but it’s remarkable how many do. So, the reasons are variable. Sometimes it’s because there aren’t other options, but sometimes it’s because it adds options or adds cards to the playing deck, if you will, and sometimes it’s just pure altruism.

I guess that’s especially true in earlier-stage diseases, where you don’t necessarily need experimental treatment or access to something that you wouldn’t otherwise get access to, such as those on active surveillance.

Dr. Madan: Correct. We have patients in studies who just have rising PSAs where we’re trying to evaluate the potential of immunotherapy in that setting, but the alternative therapy is just really observation for a lot of those patients. For them, the trial is an opportunity to do something when the standard of care might be to do nothing.

What about the concept of the placebo? I’ve heard patients say they’re afraid of getting a placebo, which could make their cancer worse. Is that still a part of the clinical trial world?

Dr. Madan: It is part of the clinical trial world. Many trials require a placebo because in order to scientifically answer a question, there may have to be a group of patients who are untreated. In those circumstances, the protocol (a document that is often over a hundred pages) is designed to protect those patients. Whenever patients are on placebos, there are very strict guidelines about how they’re watched and the parameters used to remove them if there’s evidence that their cancer is getting worse. In some cases, they have scans very frequently. They’re not left unminded, and it’s usually for a short time.

But many trials don’t involve placebos. We conduct trials to see if we can take a standard therapy that’s in use and add something to it to make it better, and this is especially true in this new age of immunotherapy.

In that process, everybody will get the standard therapy, and some of the patients will get the experimental therapy in addition.

They’re not just getting a placebo, and then left unmoored.

Dr. Madan: Right. There are very strict criteria about how patients are monitored so that, if there is evidence that the cancer is getting worse—regardless if it’s standard therapy or placebo—then they move onto something else. In many trials with placebos, oftentimes the physicians don’t even know what the patients are getting, so the physicians often treat them all like they’re getting the placebo because that’s really the safest thing from a patient’s standpoint.

That’s interesting.

Dr. Madan: We need to monitor placebo patients closely in case they are getting nothing, and we need to move on to something else. But if a trial involves placebo, patients should be comfortable with that and comfortable with the relationship with their doctor who’s going to help them make these decisions. Otherwise, it creates a lot of stress, whether in the initial process with the randomization or while they’re on the study.

What about the financial end of trials? Do patients have to pay to participate in clinical trials—for the therapy itself, the procedure, the scan, or more? Or are the costs just travel expenses and time away from work?

Dr. Madan: Generally speaking, patients don’t pay the price for the drug treatments on a clinical trial. Sometimes trials are billed so the insurance company will cover standard costs that would be covered anyway. But for the most part, the patients do not incur the cost of the clinical trial. Costs are borne out by the companies or research bodies that conduct the trials.

Here at the National Cancer Institute (NCI), we are able to conduct trials that are completely free of charge to the patients. And in addition to that, because we are a government entity designed to really benefit the entire country, once patients are enrolled in our trials, we are able to fly them in from different parts of the country.

We can incur the travel costs for patients who travel from anywhere in the United States. That’s part of our mission here: to bring the benefits of this institution to everyone in the country.

Wow! So your clinical trial patients only have to pay for their hotel and time away from work?

Dr. Madan: Correct. And most patients qualify for a subsidy toward their hotel.

That’s unusual, isn’t it? Most non-government- funded trials don’t offer things like that, do they?

Dr. Madan: Yes. It’s an unusual circumstance. It allows our institution to address diseases that may not affect many patients within one geographical area. It’s a unique opportunity to conduct studies on rare diseases, but we also use it for studies in more common diseases.

You don’t want to just study prostate cancer in men in the metropolitan D.C. area, right?

Dr. Madan: Correct. For example,

I have studies with medullary thryoid cancer, which is a very rare disease. But we’re able to get people from across the country and do it in a way that no other institution can because our catchment area is the entire country.

How can men find out about clinical trials? My impression is that the usual path is that their doctor brings it up, or perhaps they hear about it in a support group, but what are some ways that men can find out about trials? Just by visiting clinicaltrials.gov?

Dr. Madan: I would actually recommend https://www.cancer.gov/about-cancer/treatment/clinical-trials/search because clinicaltrials.gov is more for clinicians. One of the greatest features of cancer.gov is you can search by zip code or city, and it tells you trials within 25, 50, 100 miles, or whatever you like. But either website has a great patient-based resources. I encourage patients to bring up clinical trial options with their doctors and get their doctors’ thoughts on what they find.

Patient support groups are another excellent resource. Depending on the cancer, there are also online support groups that are more prevalent and will probably become more so. Over about a third of our patients are self-referred from around the country, and not just referred by doctors, so it’s common for patients to advocate for themselves in this manner.

I was under the impression that if, for example, a man found one of your trials on clinicaltrials.gov and thought he was a perfect fit, he had to go back through his doctor to get involved in the trial. Is that true? Or can he contact you or the researcher directly?

Dr. Madan: Yes; he or she can contact the researcher directly. I get some calls directly from patients saying they saw this on the internet. We also have a clinical trials contact, so no, they don’t have to go through their doctor. I often encourage patients to speak to their doctor just to get an impartial perspective or additional perspective.

Also, patients and doctors have very good relationships usually, and it’s important to get a second opinion before you embark on the clinical trial journey.

But certainly they can contact us directly, and they very frequently do.

When studies are finally completed and published in academic journals, are patients informed, or do they have access to those results?

Dr. Madan: There’s not often a direct mechanism by which patients are informed about the results of the trial. But often, through the course of a study, patients will ask about the experiences so far. We’ll certainly fill them in, and then we have had patients call us up for results. We certainly publish the results and can share them, but there’s not a direct mechanism.

Interesting. There probably should be.

Dr. Madan: That’s an interesting idea. It’s possible some institutions have that. I’m not aware of any at this time.

But patients can always ask their contact directly, right?

Dr. Madan: Yes.

What else should patients know about joining clinical trials?

Dr. Madan: Clinical trials can be an important part of each patient’s individual treatment strategy. Especially for patients with cancer, it’s important for them to develop these strategies in conversations with their doctor and their families, and to develop that strategy based on personal preferences.

Clinical trials are a way to get additional treatment options over time, options beside the standard options that are generally available. Being on a trial requires a little additional time, and there is potential for side effects. If there’s a randomization process, patients should be comfortable with that, no matter what they get.

As the patients who come to NCI from all over, consider local trials and those around the country. Sometimes travel is not optimal, but we’ve had patients come in from as far away as Hawaii and Alaska. Take advantage of the opportunity if you can. The pace of cancer research today is remarkable, especially in immunotherapy, which is one of the biggest focuses here at NCI.

All of us should remember that none of these advances would have happened without remarkable patients who decided to enroll in clinical trials. I consider it an honor to be able to work with the types of people who enroll in trials here at NCI and around the country. It’s really an extraordinary and humbling experience for me.

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Funding Clinical Trials

Dr. Jonathan Simons is the driving force behind the Prostate Cancer Foundation, one of the leading funders of prostate cancer research worldwide.

Prostatepedia spoke with him about what clinical trial participation can do for your own prostate cancer journey.

Join Prostatepedia to read more about prostate cancer clinical trials.

How did you become involved with prostate cancer advocacy and the Prostate Cancer Foundation (PCF)?

Dr. Jonathan Simons: When I joined the Johns Hopkins faculty in 1993 as a young assistant professor, perhaps six laboratories in the world had prostate oncologists trained in molecular biology. Johns Hopkins did not have even one clinical trial in advanced prostate cancer using a medicine actually designed to fight the disease.

Then I met Mike Milken. He’d been diagnosed with advanced prostate cancer and was seeking third and fourth opinions—not only about his own case, but the state of prostate cancer research in general. Mike wasn’t new to medical philanthropy; he’d been funding a broad range of research for decades before his diagnosis. But he was new to prostate cancer, so it was encouraging when he left our meeting saying there would be an infusion of research funds and a foundation to make progress against this disease. My mentor and research director at Johns Hopkins, Dr. Donald Coffey, told me, “If anyone’s going to change this field, he’s the guy. I didn’t realize that later I’d end up being PCF’s CEO and President.

You were quite young.

Dr. Simons: I was an Assistant Professor eight months on the Johns Hopkins faculty, and I had a six-year-old and a four-year-old son running around in my office with coloring books on weekends while we set up experiments in my small laboratory. Back then, I was funded by PCF from across the hallway. They were within shouting distance. I have now a 30-year-old and a 28-year-old who do not use crayons.

What year did you officially join PCF?

Dr. Simons: I was there at the beginning in 1993 and was invited to the inaugural celebration of the founding in Washington, DC. Early funding from PCF allowed me as a physician-scientist to train in my laboratory another generation of young investigators who have gone on to become chairpersons and full professors at leading cancer institutions. Today they work toward better precision treatments and cures for prostate cancer in fields ranging from molecular biology to drug development, early clinical trials and nanotechnology. In 2007, I was recruited from the Emory University Cancer Center as its Founding Director and appointed CEO and President of the Foundation. I feel an awesome responsibility and the privilege to continue to serve the field in this way.

PCF funds quite a bit of research, both in United States and abroad. Is there a theme behind the kind of research you fund? What is your overall strategy?

Dr. Simons: The overall strategy is to fund the world’s best, most innovative ideas early enough to reduce deaths from prostate cancer, reduce suffering from prostate cancer, and ultimately eliminate prostate cancer as a plague on humanity. What that means, though, is that we fund mostly laboratory-to-clinic, game-changing, early-stage research in university and cancer center laboratories. We find partners to leverage this funding with additional government or biopharma support. We also fund research to help guide those therapies into the clinic to test whether they are successful or not.

If the treatment shows promise, we try to leverage further the tens of millions of philanthropic dollars that we put in at the beginning with hundreds of millions more from Department of Defense, National Cancer Institute, Stand Up 2 Cancer, the V Foundation, and private foundations. About 80% of what we fund is precision treatment science, 10% basic biology, and perhaps 10% prostate cancer prevention including precision nutrition research.

Additionally, PCF was established with more in mind than accelerating cure for prostate cancer. From the beginning, we aspired to change the face of cancer research and to produce results that could help people suffering from a broad range of serious diseases. We never saw the process as a zero-sum game where increased funding for one disease diminished support for others. Rather, it has always been one of our key goals to increase the size of the research pie in ways that would benefit the greatest number of people.

Your organization funds the beginning idea—sparking research—and then other organizations like pharmaceutical companies or research institutes take the ball and run with it?

Dr. Simons: That’s exactly so. Spark, instigate, cultivate scientific proof-of-concept, and convene stakeholders to ensure there is a strong ecosystem to take those concepts forward for patients.

You partner with pharmaceutical companies. You partner with medical institutions and the United States government. What about other countries? Do you work with groups in other countries?

Dr. Simons: We fund research in 21 countries. We have working partnerships with five foundations. We usually lead invest, but we are delighted to co-invest in research, particularly new kinds of treatment. We should really be called the Global Prostate Cancer Foundation.

It has been difficult for researchers to get patients to enroll in clinical trials. Why do you think that is? What has been the obstacle to getting men to participate?

Dr. Simons: It is complex. I wish I knew all the answers. I think one reason is that patients feel fear about receiving a placebo and about being a guinea pig. That almost never happens in the kind of treatment research that we fund.

But I also think there is a lack of access to information about trial availability. I still think patients aren’t empowered to ask which clinical trials could help them have a better outcome and also help others. I don’t think the system is proactive. (Crate and Barrel bothers me a lot more about their products than the National Cancer Institute bothers patients about whether or not they might be eligible for a precision medicine trial.)

We’re trying to increase awareness of these newer precision medicine clinical trials that have a much higher probability that the drug will work because the target gene is expressed or mutated. Basically: your tumor is vulnerable now and we’re getting access to it, so the investigational drugs have a real chance of getting you back into remission. I think those are the major challenges.

Another issue is distance and travel time and associated costs. Clinical trial participation goes way down if it takes the patient more significant time to get to the hospital. If you are enrolled in a clinical trial, you have to go back and forth more often to see the doctor and nurses monitoring you. With a longer commute, participation rates fall. We’re therefore very interested in telemedicine, or using the internet, so patients don’t have to drive as much. That’s still experimental. Dr. Matthew Galsky, from Mount Sinai, is working on that problem.

Using telemedicine in clinical trials?

Dr. Simons: Yes. Most everything in the clinical trials world is still analog, and yet we live in this extraordinarily digital age. I’m talking to you on my phone—a piece of glass with some metal off ultra high frequency radio waves. Right before this call I was looking at an MRI scan on my iPhone. I can do that, but we still make patients drive 90 minutes to see a doctor when we could probably use a smartphone.

There are a lot of ways we could very reliably take care of patients in an outpatient fashion. We just haven’t fully digitized clinical trials, particularly for patients at a distance. There are a lot of ways to innovate around digital healthcare that would help make clinical trials easier for prostate cancer patients.

I think some men assume that a clinical trial might not be an option until their cancer has advanced. They wait until things have gotten really bad and then they look for a trial. I don’t get the impression that many people think about trials when they’re first diagnosed.

Dr. Simons: No.

But there are trials for the newly diagnosed, aren’t there?

Dr. Simons: Absolutely. And a lot of them offer the possibility of much greater longevity and survival. Your instinct should be: where is the right clinical trial? But you’re still processing, thinking, “My God, I have cancer!” We could do a much better job of educating patients.

How do most people find out about clinical trials? Just waiting for your doctor to say that she has found a trial you might want to consider? Or is the burden on the patient to find the trial?

Dr. Simons: Most of the time, if your physician isn’t a real champion, it’s just not a part of the consultation. Most clinical trial enrollment happens because you have a urological oncologist who believes in putting patients on clinical trials and is probably participating in one. We’d like patients at every stage in their journey to look for a clinical trial with the idea that it might offer a better plan of care than they would otherwise have. We could also do a better job of encouraging nurses to talk with patients about clinical trials.

How would you suggest men look for trials?

Dr. Simons: The site http://www.clinicaltrials.gov is an excellent place to look. I think www.PCF.org is an excellent place to look as well. Making a habit of asking your doctor if there are any new clinical trials for where you are is also a great idea. Create the expectation that your doctor has to pay attention to potential trials.

The site http://www.clinicaltrials.gov tends to be a little bit technical. I would think it might be difficult for the average person to sort through.

Dr. Simons: You can always just ask your nurse or doctor about it. But I agree. We put more than 82 cents on the dollar into our research mission every year. But we wish we had the resources to create an incredibly patient-friendly, readable, real-time, digital website for clinical trials. Until somebody does that, clinicaltrials.gov and pcf.org are good places to find the really important trials.

I suppose you could always come up with a list of trials and then bring it to you doctor and ask if any are appropriate for you.

Dr. Simons: Yes. For right now, that is the best thing to do. The first thousand men cured of advanced metastatic prostate cancer will all be on a clinical trial. That’s a true thing. This is how we talk to lymphoma patients. It’s just more and more possible to talk about it for prostate cancer.

Prostate cancer is undergoing a revolution that other cancers have already gone through?

Dr. Simons: We’ve cut the death rate down by 52%. That’s incredible. For the last 48%, we’re going to need clinical trials. We need patients on clinical trials to take the death rate to zero. Sometimes prostate cancer, unfortunately, escapes surgery or radiation and comes back. While we’ve significantly increased the overall survival rate, we’re not yet able to cure the majority of men. We think we can. We know we can, but we have more work to do.

What does the financial end of clinical trial participation look like? Do men have to pay a fee for the therapies?

Dr. Simons: In clinical trials, research drugs are always free. Medical care is always free. The inconvenience is what is costly. Some employers are very difficult about you missing work for a clinical trial. There is a lot of going back and forth. They call it wage and financial toxicity. One of the effects of the experimental drug is toxic to job security. (It’s hard enough when you’re a cancer patient and worried about your employer.) But the drugs, the pharmacy, the medical care, and the scans are all free.

Is there anything else you think patients might want to know about clinical trials?

Dr. Simons: The misperception is that patients will be treated like guinea pigs. But the first thousand patients cured of prostate cancer will all be on a clinical trial. Every major clinical trial is changing prostate cancer patient survival.

For example, in the SPARTAN trial for Erleada (apalutamide), the drug was so effective that within two weeks of presenting the results, it was FDA-approved. That’s a record. Data was presented showing that 800 patients were benefitting from the drug, and then it was approved.

The only drug that gained approval that quickly in all of oncology was Soltamox (tamoxifen) for breast cancer. We think this is going to happen all the time now.

The SPARTAN Trial focused on patients for whom previously there were no treatments. They saw their PSAs going up, but they were not metastatic. There was really nothing for them to do except wait until we started seeing metastases.

Now, with Erleada (apalutamide) there is a chance that they’re not going to see metastases for years. They’ve got hope. For that first group of men, all of this is possible because they found that clinical trial. Hundreds of men who participated in the SPARTAN trial are going to have a prolonged time without metastases.

Would you encourage newly diagnosed men to seek out clinical trials, even if their cancer is under control?

Dr. Simons: Yes. I encourage every patient to think about joining a clinical trial. It’s not an easy message, but there are many studies showing that you get better nursing just by being on a clinical trial. You just get more attention. You can be there for the cure.

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