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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 Clinical Trials

Dr. Charles Myers frames our May conversations about prostate cancer clinical trials:

Over the past ten years, the management of prostate cancer has been revolutionized by the appearance of new drugs and new concepts using established drugs as well as surgery and radiation. Every one of these advances only exists because of clinical trials. This is the only path forward. This month, we discuss many of the issues patients face when they consider entering a clinical trial.

The fact that most large clinical trials include a randomization to a control arm is often a major source of patient concern, especially if the control arm uses a placebo. When the control arm involves an active treatment, that treatment will typically represent current state-of-art care that you might receive if you do not enter a clinical trial. However, the cost to you will be less because the clinical trial sponsor will commonly cover the cost of care. The financial benefit to you could easily reach thousands of dollars.

What if the trial includes a placebo arm? First, the existence of a placebo arm commonly indicates that no existing treatment has proven to be of benefit. As a patient, you should do your due diligence on this point. Second, there are strict rules in place to protect patients on the placebo arm. You should know these rules and make sure you are comfortable with them.

Patients on a trial’s placebo arm commonly do better than similar untreated patients not on a clinical trial. There is actually a large literature on why the Placebo Effect exists.

One explanation offered is that patients on the placebo typically get better standard care, and I think this is a major factor. It may also be that patients on placebo do better for psychological reasons or a mind-body effect. The latter might be particularly relevant for the treatment of nausea, pain, anxiety, or depression.

Finally, many patients enter clinical trials for altruistic reasons. By entering a well-designed clinical trial, you will help answer questions that will benefit future patients. The progress we have made over the past decade only happened because patients who came before you chose to enter clinical trials.

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Dr. John Gore: Why Medicine?

Dr. John Gore is a clinician, surgeon, researcher, and educator specializing in urologic oncology and general urology at the University of Washington.

Prostatepedia spoke with him about how Decipher changes the way doctors treat men with prostate cancer.

Why did you become a doctor?

Dr. John Gore: My initial vision for my life was that I was going to be a lawyer. Then I found that I really enjoyed my experiences while interning at the hospital. That brought about an application to medical school. I think being a doctor offers a chance to have a daily meaningful impact, which is a unique part of the job.

How did you end up working in urology?

Dr. Gore: Urology is a specialty that very few people enter medical school thinking that they want to do. In part, most people are like I was and don’t even know about the specialty. I don’t have any doctors in my family. The only doctor I knew was my own pediatrician. I just assumed I was going to be a pediatrician.

But I really enjoyed surgery. I enjoyed being in the operating room. I just really enjoy the generic construct that someone has a problem and I have the tools to fix it.

Urology is an interesting hybrid. Most surgeries have a homolog in internal medicine. For example, there’s cardiothoracic surgery and cardiology. There’s colorectal surgery and gastroenterology. We don’t really have that in urology. We do a lot of chronic disease management. We do a lot of long-term follow-up of our own patients. It is, in many ways, a hybrid of internal medicine and surgery, which is really cool.

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Dr. Eric Klein: Why Medicine?

Eric A. Klein, MD, is an international leader in the biology and management of prostate cancer. Dr. Klein serves as Chairman of the Glickman Urological & Kidney Institute at the Cleveland Clinic.

Prostatepedia spoke with him about why he became a doctor.

Why did you become a doctor?

Dr. Klein: I don’t really know. I never remember wanting to do anything else.

Even when you were a little kid?

Dr. Klein: When I was in first grade, I missed a month of school because I had what they thought was rheumatic fever. My pediatrician came to see me a couple times a week. That doesn’t happen so much now.

No. It doesn’t.

Dr. Klein: I suspect that’s had some influence because my parents really respected him. But I can’t articulate it for you. I never wanted to do anything else. It was not an intellectual decision. It’s just what I wanted to do. I was born wanting to be a doctor.

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Dr. Felix Feng: Why I Became A Doctor

Dr. Felix Feng is a physician-scientist at University of California, San Francisco (UCSF) keenly interested in improving outcomes for patients with prostate cancer. His research centers on discovering prognostic/predictive biomarkers in prostate cancer and developing rational approaches to targeted treatment for therapy-resistant prostate cancer. He also sees patients through his prostate cancer clinic at UCSF.

Prostatepedia spoke with him about why he became a doctor who cares for men with prostate cancer.

Why did you become a doctor?

Dr. Felix Feng: I became a doctor because my family has a strong history of cancer. Unfortunately, I learned the repercussions of cancer at an early age. All four of my grandparents passed away from some form of cancer. My father has successfully overcome three different cancers. Just last year, my sister, unfortunately, passed away in her 40s from cancer.

Before ever becoming a doctor, I was part of many patients’ families. I saw it strongly from the patient side and decided that if I was going to commit my life to studying something, it was going to be cancer.

So then your journey is really personal.

Dr. Feng: Very personal.

Join us to read Dr. Feng’s thoughts on genomics + prostate cancer.

 


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Genetic Testing + Counseling

Ms. 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 talks to Prostatepedia about guidelines for genetic testing in men with prostate cancer.

Much has been written or suggested about the genetic component of some prostate cancers. For example, a family history of prostate cancer can increase a man’s risk of such a diagnosis. There have also been articles about the genetic component of certain breast cancers: BRCA1 and BRCA2 have historically been strongly implicated in the familial pathway for that diagnosis. What is more recent is the now more-firmly established connection between certain mutations like BRCA1 and BRCA2 and prostate cancer. However, guidelines for genetic testing in men with prostate cancer have been limited.

Recently, the Journal of Clinical Oncology published a special article entitled “Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017” following the Prostate Cancer Consensus Conference held in Philadelphia on March 3-4, 2017. Members of the panel strongly agreed that men should engage in shared or informed decision-making on the issue of genetic testing.

Panel members emphasized the strength of the inherited predisposition of prostate cancer, noting higher risks with BRCA1, BRCA2, and HOXB13 genes. The panel noted that prostate cancer patients with BRCA2 mutations have poor prostate cancer-specific outcomes. We now consider the link between prostate cancer and DNA mismatch repair (MMR) gene mutations to be stronger than we suspected, adding a specific opportunity for treatment. In fact, up to 12% of men with metastatic prostate cancer have inherited genetic mutations, mostly with BRCA1, BRCA2, and ATM. And targeted agents for these specific mutations confer better outcomes for these patients.

The panel concluded that: “Identifying genetic mutations of inherited prostate cancer… has implications for cancer risk assessment for men and their families, for precision treatment of metastatic disease, and is being incorporated into guidelines for individualizing prostate cancer screening strategies specifically for male BRCA1 and BRCA2 mutation carriers.”

Unfortunately there are no generally accepted standard guidelines for genetic counseling and genetic testing in prostate cancer, or standards on how to fully interpret results of current panels with multiple gene testing. The information discovered through genetic testing not only informs treatment for the prostate cancer patient himself, but is also an aid to other members of his family, including women who may have a genetic disposition for developing breast cancer. As for the patient, not only does the information potentially help guide prostate cancer treatment, but it also makes both him and his clinician aware of the potential for additional cancers.

The results of the Philadelphia Prostate Cancer Consensus Conference can be read in detail in the Journal of Clinical Oncology 36, no. 4 (February 2018), 414-424. Their considerations included the following:

  • which men should undergo genetic testing for prostate cancer;
  • which genes should be tested based upon clinical or family scenarios;
  • how the testing results should be used to inform screening for prostate cancer; and
  • how results should be used to inform treatment of early stage (localized), advanced stage (high-risk), and metastatic prostate cancer. Genetic testing done thoroughly and properly can help guide screening and treatment decisions.

The National Alliance of State Prostate Cancer Coalitions strongly endorses the use of genetic testing and genetic counseling for prostate cancer, and urges clinicians to read, consider, and follow the scientifically sound suggestions of the 2017 Philadelphia Prostate Cancer Consensus Statement on the Role of Inherited Prostate Cancer Risk. NASPCC will be presenting a Webinar on Genetic Testing and Genetic Counseling in Prostate Cancer on May 9, 2018. It is supported by Myriad Genetics. (Visit https://naspcc.org/index.php/may-9-2018-naspccwebinar to register.)


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Patients Help Shape Prostate Cancer Genomics Study

Joel Nowak is a prostate cancer patient and well-known prostate cancer activist.

Prostatepedia spoke with him about his involvement with the Metastatic Prostate Cancer Project.

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What is the Metastatic Prostate Cancer Project?

Mr. Nowak: This is a joint project between the Broad Institute and the Dana-Farber Cancer Institute. But what is really more important to me is the researchers who are involved: Dr. Corrie Painter and Dr. Eliezer Van Allen are really committed to what they’re doing. They’ve modeled this project off of a metastatic breast cancer project that they also started.

One of the researchers is a cancer survivor, so they understand what it means to have cancer. Their understanding motivates what they’re doing. They’re carrying it forward; they’re not just doing it because they have a grant.

How did you come onboard with the Metastatic Prostate Cancer Project?

Mr. Nowak: My friend Jack Whelan, who I’d worked with at the American Association of Cancer Research Scientist↔Survivor Program, had a very rare blood cancer. Then one day he surprised me by saying he’d been diagnosed with prostate cancer. I thought he was joking at first.

Unfortunately, his cancer progressed really quickly, probably related to all the treatments he had for his blood cancer. The project staff brought me, Jack, and Jan Manarite in to work on the project. They asked me to look at their materials and give a patient’s perspective. They wanted to know if I found value in the project

They asked me to give them specific feedback and suggestions for improvement. Jack, Jan, and I have also brought in two others. Dr. Van Allen’s team has taken all of our suggestions and made the changes.

They also asked us to spread the word, let people know about it, reach out within the prostate cancer community, and help recruit.

What is it about the project that makes it patient-friendly?

Mr. Nowak: The project is patient friendly because once someone consents and says, “Count me in,” the project team does all the work. They send out a package, which we advocates helped redesign, and you just contribute your spit. Then you bring your sample back to the post office or FedEx; it’s all prepaid. Spit it and ship it. That’s the effort.

We also send out blood vials that are also prepaid. Theoretically, you can walk into a lab and they’ll draw your blood for free. Or you can bring the vials to your next doctor’s appointment. You don’t even have to make a special appointment; just ask them to draw an extra tube.

It’s easy.

Mr. Nowak: Yes. It’s easy, and it’s all prepackaged. Either you or the phlebotomist can just put it into the prepaid package and send it off. You don’t have to do much.

Part of the consenting process is the release of the medical records. The project does the sequencing of the blood and saliva, and if applicable, we ask for tissue. There’s not a lot of tissue in prostate cancer, generally, so that was one of the issues I brought up. I wanted to ensure that no one’s tissue is used up and withheld from them for the purposes of this research, because you never know when we’ll need your own tissue for treatment decisions. We advocates said this was a big issue, so the project will only use a small piece and return it. You need to get it back: you just never know when you’ll need it yourself.

You need to look out for yourself.

Mr. Nowak: Yes. It’s appropriate to be selfish in this particular situation. The only thing you have to do as a patient is read the consent, discuss it with the appropriate people at the project, sign the paperwork, spit, and bleed. That’s all we have to do. Everything else is handled by the project. You don’t even know it’s happening; it’s all behind the scenes.

This is a research project, not a clinical trial, but even with clinical trials everything gets de-identified. That means that your personal information is safe, but you also get no follow-up information. As a patient advocate, I asked what they could do to give some feedback to patients. They were very open to having this conversation, but they are sensitive about overpromising anything. We don’t want to mislead anyone.

If we start seeing trends in the data, we will give some feedback. We can’t tell individuals that they have gene mutations or not, for example, because their sample was de-identified. But if, hypothetically, we see samples from 300 people with a combination of at least three gene mutations and that 285 people with a particular mutational sequence respond to Xtandi (enzalutamide) but not to Zytiga (abiraterone), then we will give feedback.

But this is exciting. When we start seeing trends or possible trends, the project will release information to people who participate. There will be aggregate data feedback. We’ll be able to publish relationships. It doesn’t of course stop me as a patient from going to my doctor and getting sequenced. Probably all of us should be sequenced anyway.

The patient can follow up as he chooses…

Mr. Nowak: Exactly. Then they could say, “I’ve been sequenced, and I have this mutation.” That is just an additional talking point with your doctor from the aggregate data. I’m excited about that. That’s going to give some people another thing to consider when deciding between treatments.

Why should men participate? Did you participate?

Mr. Nowak: I did. Jack and I fought over who would be Patient 1. I had respect for Jack, so I told him he could be Patient 0, and I’d be Patient 1. Technically, I’m Patient 2. Men should participate for a number of reasons. First of all, we have to think about the next generation. My prostate cancer is genetically linked. My father had it. His brother died from it, and his only child, who’s older than I, who had been treated. My grandfather had prostate and breast cancers, and my great-grandfather died of prostate problems. Many of us have or are going to have kids, so we should make it a little better for them if we can.

I spend a lot of time working with people and helping them figure out how to have a conversation with their doctor about treatment. Anything that can give us more information and more points of conversation is important. Aggregate data might help us have better conversations that may help make better decisions going forward.

This is one of those rare research projects where I could possibly benefit directly. As I start going through treatment protocols and so forth, I have no idea where they may find something that works better for me. It’s just going to guide my decision-making. Maybe it’ll extend my life because I made a better decision thanks to the project.

We also need to understand cancer more generally in terms of genetics and its microenvironments. We need to understand cancer not only as separate diseases. Prostate cancer only describes the organ from which the cancer originates. It doesn’t really describe my disease or another’s. We need to drill down and understand the type of prostate cancer that one has and how it relates to cancer generally. That is going to guide us in making better decisions.

This type of research is invaluable. There are no risks. There is nothing invasive. The more we understand, the better future research will be, whether for specific treatments or a better understanding of biomarkers, which we have a terrible dearth of knowledge about. To me, it’s a no-brainer for us who are going to benefit at no cost.

I hope men sign up.

Mr. Nowak: Yes. That’s our goal. Now that we have IRB (Internal Review Board) approval, our next step is to get men signed up.

To participate visit https://mpcproject.org/home

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