Chemotherapy, Xtandi, and Zytiga

Dr. Julie Graff is a medical oncologist at Oregon Health & Sciences University.

Prostatepedia spoke with her recently about chemotherapy, Xtandi (enzalutamide), and Zytiga (abiraterone) for prostate cancer.

Why did you become a doctor?

Dr. Graff: Even as a child, I wanted to become a doctor, so my whole life I thought about it. Then I went to college, I fell in love with science, and I thought I would get a job somewhere working in a lab.

During college, I volunteered for a hospice, and I realized how much I love patients, how special people are, and how people with cancer are among the strongest people. I was drawn to work with them, and also, my scientific side could still be engaged in research.

Have you had any patients over the years who stand out in your mind as having either changed how you see your own role as a doctor or how you view the art of medicine in general?

Dr. Graff: I’ve had multiple patients who’ve meant a lot to me over the years. Someone I met in hospice stands out. The first time I met him, he said, “I know that I’m 80. You look at me, and what you don’t realize is that I want to live just as much as you do.” He had emphysema and was dying, but the drive to live can stay so strong, even at 80. Your body’s not even working that well anymore, and you’re suffering. Still, just this drive to stay alive is important. I’ve kept that in mind since then.

On the other hand, I’ve had some patients who say that years don’t matter—it’s quality of life. I can appreciate both sides. When I talk to patients, even those who say they want to live forever, I tell them that what we want to do is help them live as long as possible while maintaining a quality of life that they can enjoy.

I guess each person falls somewhere along that spectrum.

Dr. Graff: Exactly. As a doctor, you really just have to educate people, and tell them, “I know you want to live and that you think it’s a good idea to get surgery, even though there’s a 50% chance you could die during surgery or whatnot. But what are your real goals, and how can we help you reach them?” We want to move the focus of the conversation a little bit.

Can you give us a brief overview of how and when chemo is used for prostate cancer. I know it’s different from how and when chemo is used in other cancers.

Dr. Graff: In prostate cancer, there are a couple of settings where chemotherapy is used. We’ve been using the drug Taxotere (docetaxel) for 15 years now. It used to be something we gave at the very end of the disease course, when the hormone shots stopped working, but as of 2015, we use it early in the disease also.

Chemo has a bad rap in some ways. It’s thought to be something you should avoid at all costs, but what people don’t realize is that, when symptoms of the cancer (such as bone pain) get bad, chemo can help. The type of chemo we use in prostate cancer is not as toxic as we do for other cancers. We just use one drug. It doesn’t cause a lot of nausea and vomiting, which is a lot of patients’ worst nightmare. We use it in early and late settings, and I don’t think anything’s going to replace it. Even though we have other drugs now, we run out of hormonal options, and chemo’s a decent option.

When and how are Zytiga (abiraterone) and Xtandi (enzalutamide) used in prostate cancer?

Dr. Graff: Zytiga (abiraterone) and Xtandi (enzalutamide) are similar to chemo in that, initially, they were used at the very end of the disease. Now they can be used up front when people are diagnosed with metastatic prostate cancer, so it depends.

Most people get some mileage out of one or the other, but there is a large degree of cross-resistance between the two. It’s not likely that people would get good cancer response out of both of them. It’s going to be interesting to see what happens to Xtandi (enzalutamide) now that there are other drugs that target the same pathway.

What is androgen-receptor splice variant 7 messenger RNA (AR-V7), and what is its role in resistance to Zytiga (abiraterone) and/or Xtandi (enzalutamide)?

Dr. Graff: The androgen receptor has several domains, and one of them is the ligand-binding domain, which is very important. As this androgen receptor floats around in the cell, the androgens (male hormones) bind to that ligand-binding domain, and so does Xtandi (enzalutamide) for that matter. Cancer cells can lose that part of the androgen receptor, then lose their dependence on the androgens that are circulating and lose the target for Xtandi (enzalutamide). The AR-V7 splice variant can predict resistance to both Zytiga (abiraterone) and Xtandi (enzalutamide), and it might be a reason why there’s cross-resistance between them.

What role does chemotherapy play in this resistance to Zytiga (abiraterone) and/ or Xtandi (enzalutamide) that we see?

Dr. Graff: Fortunately, chemotherapy is still active in people whose cancers are resistant to Zytiga (abiraterone) and Xtandi (enzalutamide), so it still plays an important role. It can be very useful when people have prostate cancer-related symptoms.

We use chemo early on in metastatic disease, right after diagnosis. There are three studies presented in the past year in which they use chemo followed by Xtandi (enzalutamide) or a drug like it. It might be more effective in combination with those other drugs. We’re trying to learn still.

Can chemo reverse resistance to Zytiga (abiraterone) and/or Xtandi (enzalutamide), or does it play any role in that scenario?

Dr. Graff: I don’t know if it can reverse it. I have seen data showing that, if you’re on Xtandi (enzalutamide) and the cancer cells become resistant to that, then if you put a patient on chemo, some of those cells that aren’t resistant to Xtandi (enzalutamide) might come back, and it might be reasonable to re-treat it then. That’s not carved in stone.

Is it being explored in any clinical trials that you know?

Dr. Graff: I hope so. I don’t know which trials those would be.

What about the side effects of these various agents?

Dr. Graff: It’s complicated. Chemotherapy can cause some low blood counts and a risk of neutropenic fever, but then it has other side effects, like neuropathy in the hands and feet, that don’t just reverse automatically. There is also some tear-duct scarring and watery eyes. These might get a little better off the chemo, but they could be permanent side effects for the patients.

This type of chemo doesn’t hurt the kidneys, you need good liver function to get it, and it doesn’t seem to cause hypertension. In those ways, chemo is a good option for elderly men with prostate cancer.

Zytiga (abiraterone) can cause mineralocorticoid excess, which means the adrenal glands aren’t functioning normally. You could get too many of one type of hormone that causes high sodium and low potassium. Zytiga (abiraterone) can also irritate the liver, so we’re careful to watch for the liver function. It can also exacerbate the hormonal side effects of castration.

Xtandi (enzalutamide) is known to cause profound fatigue, which was its dose-limiting toxicity. Of course, it’s linked to seizures, but in people without a history of seizures, that’s pretty unusual. And just like Zytiga (abiraterone), it can cause hypertension. Management of blood pressure and cognitive decline is critical. People have reported that they feel a bit foggier on Xtandi (enzalutamide), and they have also reported increased falls, especially in the elderly. Once you’re off Xtandi (enzalutamide), some of those things will reverse, but it’s possible that being on Zytiga (abiraterone) and Xtandi (enzalutamide) could result in muscle mass loss or other things that won’t recover off those treatments.

What would you suggest to manage those side effects?

Dr. Graff: Exercise is critical for any prostate cancer patient. The drugs we use—even just the initial hormone therapy of turning off the testicles —lead to so many side effects like thin bones, muscle loss, weight gain, and all those things can be mitigated with some exercise. They won’t be taken away, but they could at least be improved. That exercise should continue on the other drugs.

It’s really hard to exercise when you’re on these drugs because you’ve got more fatigue. A lot of patients with prostate cancer have arthritis or some barrier to exercise that makes it difficult for them, but as much exercise as possible is important.

I guess any exercise is better than none, right?

Dr. Graff: Exactly.

Do you have any further thoughts about chemo, Zytiga (abiraterone), or Xtandi (enzalutamide) that you think patients should know about or might not be aware of?

Dr. Graff: They’ve been out for a while now. Any prostate cancer patient starts with a blank slate and has to learn all this stuff with the help of the provider. Think about your goals in life and if these drugs are going to interfere with those. If your goal is to continue working as an architect or something that requires a lot of thought and careful planning, maybe Xtandi (enzalutamide) is not the best choice, and maybe Zytiga (abiraterone) is a better choice.

Some of these drugs are contraindicated in certain patients. A patient with bad heart function, like congestive heart failure or something, should not be on Zytiga (abiraterone), and a patient with a history of seizures should not be on Xtandi (enzalutamide). A lot of thought should go into picking these. The first drug you use is likely to be the most effective, and then as you go down the line, they become less effective.

As a prostate cancer patient, you have several options now; it’s not just chemo or nothing once the prostate cancer becomes resistant to the androgen blockade. Consider lifestyle when making a choice.

Not a member? Join us.

Advertisement

Dr. Tanya Dorff On Chemotherapy For Prostate Cancer

Dr. Tanya Dorff is a medical oncologist who serves as associate clinical professor in the Department of Medical Oncology & Therapeutics Research and the Head of the Genitourinary Cancers Program at City of Hope, a research and treatment center for cancer based in Duarte, California.

Dr. Dorff’s research interests in prostate cancer range from clinical trials in PSA-recurrent prostate cancer to the role of fasting in chemotherapy tolerability to CAR T cells that are primed to target prostate cancer tissue.

She leads one of the largest clinical trial portfolios in genitourinary cancers.

Dr. Dorff spoke with Prostatepedia about chemotherapy for prostate cancer.

Not a member? Join us.

Why did you become a doctor?

Dr. Tanya Dorff: When I was around three years old, I decided that what I wanted to do with my life was help people. And being a concrete thinker as a three-year-old, I felt like being a doctor was the only way to do that.

Have you had any patients over the years who have changed how you view the art of medicine or how you view your own role?

Dr. Dorff: There are so many who have influenced me. My mom had a rare form of leukemia when I was in college. It was uniformly fatal. But they had recently developed a new treatment with the discovery of a specific translocation of the retinoic acid receptor for acute promyelocytic leukemia (APL). All-trans retinoic acid was developed, and she received it as experimental (at the time) through compassionate access. She was cured, and she’s still alive today. That influences how I feel about clinical trials and translational science. If we hadn’t understood that biology, we couldn’t have designed the overwhelmingly effective treatment.

How is chemotherapy used today for men with prostate cancer?

Dr. Dorff: When I started treating prostate cancer, chemo was pretty much our only tool besides standard hormone therapy. It worked, but it was sort of end-of-the-line. People didn’t tolerate it very well, in part, because we used it in really advanced cases. Then, the drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) came out, dramatically improved the situation for prostate cancer patients, and chemotherapy got pushed later and later.

The CHAARTED study was presented five years ago. That study showed that using chemotherapy early with the initiation of hormone therapy dramatically improved survival, above and beyond using it later. About 75% of the patients on the control arm got the chemo when they became resistant, so it was a pretty good experiment of now versus later, and not now versus never. To see that just using it early added an extra year or more of life for these men was really profound. That reinforced the strong role chemotherapy has in this disease.

With which other kinds of agents is chemotherapy frequently combined?

Dr. Dorff: Combinations with Taxotere (docetaxel) have never yet been successful in prostate cancer. There was Taxotere (docetaxel) with a high-dose Vitamin D, which was not only negative in that it failed to improve outcomes, but patients who received the combination actually fared worse. There was Taxotere (docetaxel) with Revlimid (lenalidomide), Taxotere (docetaxel) with atrasentan, Taxotere (docetaxel) with GVAX… All of these combinations have failed.

One of the ASCO presentations that prostate cancer physicians might remember most vividly is a slide presented by David Quinn in his presentation of the negative results of the SWOG S0421, the study of Taxotere (docetaxel) alone or with atrasentan. He showed a slide of a graveyard, implying that any drug tried in combination with Taxotere (docetaxel) is doomed to fail.

Why do you think that is? Is it just that the combination is too toxic?

Dr. Dorff: I don’t know. I don’t think it’s too toxic. All of these combinations go through safety before they go into Phase III, and you can combine them safely. I do not understand why combinations fail. Maybe it goes back to biology. Why would the combination succeed? You want something that makes the chemo work better, or you want the chemo to make the drug work better. That’s where we should probably start when planning combination studies. Even then, things that look good in early testing can fail in Phase III, so in some cases it may be that we need to sub-classify patients in order to design more successful trials.

Maybe a more interesting question when we’re talking about combinations is: how do we get the best use of the chemo and do the least damage to the patients?

At University of Southern California, we started a study looking at a fasting-mimic diet to make the Taxotere (docetaxel) better. We found preliminary evidence that fasting prior to chemotherapy reduced toxicity, and I envision that could have two specific benefits in men with prostate cancer who might get Taxotere (docetaxel).

One might be that if we could mitigate toxicity, more men would actually receive it. There was a lot of therapeutic nihilism out in the community about how chemotherapy doesn’t work so well for prostate cancer, or that these older patients can’t handle it. If we could ratchet down the toxicity, maybe more prostate cancer patients would actually get chemo.

The second benefit might be that if we could reduce toxicity to normal host cells, we would be more likely to get in full doses on time, which might make it work better against the cancer versus what happens now, which is that we frequently dose-reduce and dose-delay because of toxicities. The fasting-mimic diet study is still ongoing but these are the outcomes I was hoping for when designing it.

How long are they fasting before they start the chemo? What does that look like?

Dr. Dorff: They fast for 48 hours on a fasting mimic diet, which means they get vegetable broth and an energy drink. So, it’s a liquid, low calorie diet. It’s hard, so that’s part of why the study is still ongoing.

In our earlier trial, in which we did fasting with platinum chemo for up to 72 hours (48 before and 24 after the chemo dose), people really swore by it. They really felt like they had so much less toxicity compared to chemo cycles in which they didn’t fast.

With the fasting mimic diet (created by L-Nutra), because it’s not pure fasting, we extended it to three days before chemo. The first day is a fairly robust number of calories, just plant based and with specific amino acids left out, which is felt to be part of the effect. Then there’s the two days before chemo with lower calories, and one day after. After fasting or the fasting-mimic diet the body needs a bridging diet for the first meal, and the L-Nutra regimen also included supplements to replenish the body.

If someone reading this is interested in participating, can they contact you directly or should they contact someone else?

Dr. Dorff: Sure, they can contact me directly at tdorff@coh.org. But the trial is going on only at USC, so they may wish to contact the clinical trials office at USC or the medical oncology group at USC.

Are you combining diet with chemo instead of another agent?

Dr. Dorff: Yes.

What kinds of side effects can patients expect from chemotherapy? What are you hoping to reduce?

Dr. Dorff: One of the most concerning side effects is the peripheral neuropathy, which can become permanent, but I don’t want to scare any readers.

Can you explain what that is?

Dr. Dorff: It’s damage to the small nerves out in the fingers and toes that can manifest as numbness or pins and needles, burning kinds of discomfort. That can be permanent.

Is there anything patients can do before or during getting chemo to reduce the likelihood of that happening?

Dr. Dorff: Not that we know of.

There’s no way to predict who might suffer from that or not?

Dr. Dorff: It’s not a complete no. We know patients who already have some preexisting neuropathy, whose nerves are already damaged, are more susceptible, for instance patients with diabetic nerve damage. That’s one reason we might try to get them Jevtana (cabazitaxel) instead of Taxotere (docetaxel) because Jevtana (cabazitaxel) doesn’t impact the nerves in the same way. I’m not sure if that’s what patients worry about, but that’s one of my number one concerns because I’ve seen patients a few years after chemo who are still vexed by the neuropathy.

If Jevtana (cabazitaxel) doesn’t result in neuropathy, why wouldn’t you use that agent over Taxotere (docetaxel)?

Dr. Dorff: Because insurance typically won’t cover it. Head-to-head, they were compared in the FIRSTANA trial, and they were equally effective; one wasn’t much better than the other. So, insurance companies can say that Jevtana (cabazitaxel) is not more effective; it’s equally effective. Taxotere (docetaxel) is a fraction of the price because it’s off-patent, and Jevtana (cabazitaxel) is actually approved specifically in post-Taxotere (docetaxel) patients, so it’s off-label to use it first-line. You can make a case when you have a guy with neuropathy, but even if you have a guy without neuropathy, you sure would like to leave him without neuropathy at the end of his treatment.

We start to see the neuropathy around dose five. If you stop, it’s more reversible, but if you keep going, that’s where it can become permanent, and so again, when we’re getting to how we can enhance the efficacy, if we could get more doses in without being limited by neuropathy, maybe we would do better with the drug, or maybe we just avoid the neuropathy, have equal efficacy and patients suffer less. There’s two ways we can win.

Equal efficacy and side effects are a huge issue for men.

Dr. Dorff: Patients really worry about hair loss. I don’t think we’re impacting that with the diet, unfortunately. That is reversible. They also complain about the taste changes and mouth sensitivity because that really impacts eating.

Does that go away once chemotherapy is finished, or does that linger after?

Dr. Dorff: That goes away.

It’s just while they’re getting chemo that they lose sense of taste?

Dr. Dorff: Yes, but it’s a long time to not be able to taste.

And the hair loss only happens while they’re getting chemo, too? It comes back?

Dr. Dorff: Yes, it grows back.

What combinations with Taxotere (docetaxel) do you think will work best?

Dr. Dorff: The ongoing combinations that I think people are still interested in are platinum with taxane and carboplatin with Jevtana (cabazitaxel). That’s an important combination for the more aggressive variants.

Part of how we think Taxotere (docetaxel) chemotherapy works is that it interferes with antigen receptor (AR) translocation in the cell to the nucleus, because the microtubules are needed for that. It still may be more for patients whose cancer is using a lot of AR signaling whereas platinum is more for cancer that might not be as dependent on that mechanism. That combination is pretty important.

There are some other biologics being studied together with Taxotere (docetaxel), but I’m not sure that those will be successful. There’s Taxotere (docetaxel) with immunotherapy, but we have the negative GVAX trial that tried combining vaccines with Taxotere (docetaxel). We are also combining it with Xofigo (radium-223), which is a little interesting, but I don’t know why those agents would necessarily help each other. Again, when you’re looking at a combination, it’d be nice if there were a reason to expect synergy.

What about favorite sequences?

Dr. Dorff: We know that after you’ve had Zytiga (abiraterone) or Xtandi (enzalutamide), you can induce the androgen receptor splice variants such as AR-V7. These are associated with less responsiveness to Zytiga (abiraterone) or Xtandi (enzalutamide). Patients might want to go from Zytiga (abiraterone) straight to Xtandi (enzalutamide), but we know there’s a lower likelihood of success, and we know AR-V7 is a big part of that. If we sequence in chemo, since they’ve shown that AR-V7 positive patients still benefit from chemo, I view the optimal sequence as Zytiga (abiraterone) or Xtandi (enzalutamide), followed by wiping out the AR-V7 population with a chemo drug, and then going to Zytiga (abiraterone) or Xtandi (enzalutamide) next. We don’t know for sure if that’s what happens when we use that type of sandwich approach, but it has theoretical appeal, and that’s how I talk to patients about it. The other way to go is a clinical trial, especially for combination with Zytiga (abiraterone) or Xtandi (enzalutamide).

What about the side effects profile when you do those kinds of sequencing?

Dr. Dorff: Hormone drugs like Zytiga (abiraterone) and Xtandi (enzalutamide) have much better side effect profiles, generally speaking, but the chemo side effects are largely reversible, and we tell patients that it’s not forever. There are good days and bad days, so it’s important to note that most people are not feeling bad every single day that they’re on the chemo. I don’t think the side effects vary based on sequence.

Some of my colleagues feel that when they use chemotherapy up front like in the CHAARTED study, they see more side effects if they start the chemo right away, but they see fewer side effects if they wait a month or two into the hormone therapy to add the chemo.

Is that because the patients become used to the side effects and learn how to manage them before you add something else?

Dr. Dorff: No, because the side effects are totally different between the two treatments. This is speculative, but I think you debulk. I think that part of the reason people get a lot of chemo side effects is that when we’re killing a lot of cancer there’s a big inflammatory reaction. You can feel sick from it, and we see that anecdotally in certain patients. If you can debulk the cancer a little bit with a couple months of hormone therapy, and then give the chemo, it might be better tolerated.

That’s interesting. So as the cancer’s dying, it throws off some kind of signal?

Dr. Dorff: It does. There’s a lot of dead stuff that has to be cleared by the body, and maybe that means it doesn’t have as much attention to do the healing that it needs to do with the chemo. I don’t know; that’s purely speculation.

Is there anything else you think men should know about chemotherapy for prostate cancer?

Dr. Dorff: First and foremost, chemo is effective. People downplay the role but CHAARTED really showed us that this is a good tool. We are working on tools that have fewer side effects. I’m working on whether diet can help mitigate side effects, and other people are looking at things like exercise, but the bottom line is that chemo is a good tool.

But still some patients draw a line in the sand and say they’ll never receive chemo because they’ve seen other patients getting chemo for other cancers. The chemo we use for other cancers is different than what we use for prostate, and every person’s reaction to chemo is different. Of course, you can’t erase that impression that’s made on you when you see someone who you care about struggling through chemo, but it doesn’t mean that’s what your experience is going to be.

Your doctor’s job, and your oncologist’s job, is to make it livable, to allow you to still do the things you want to do and to keep you safe and healthy through your chemo. There are tricks up our sleeves that we use to make that happen.

Sometimes patients are surprised to hear that they can actually feel better on chemo.

Why would that be?

Dr. Dorff: Because sometimes the cancer’s driving their side effects. It’s a catch-22. There are patients who might want to wait until they’re feeling better to get chemo, but if they’re feeling bad from the cancer, it’s really the chemo that’s going to make them feel better.

I have patients who’ve been unable to eat, in too much pain to really get out and do anything, and when they start chemo, they feel better, they eat better, they have more energy, and they can do more. If you take someone with no cancer symptoms, sure, the chemo’s going to make them feel worse. But if you take somebody with cancer symptoms, they may actually feel better.

That’s interesting because there’s this whole cultural perception of chemo as being catastrophic. The idea that chemo would make you feel better seems bizarre, but it makes sense the way you explain it.

Dr. Dorff: Yes, I think a lot of patients are shocked to hear it, and I think that’s a good thing to put out there.

Do you have any suggestions for men as to how to handle side effects before going into it?

Dr. Dorff: Communication with your doctor is the way to be successful in your chemo. A lot of people don’t want to bother the doctor, or they want to tough it out, but the earlier they tell the doctor that there’s a side effect, the easier it is for the doctor to intervene and reverse it. There’s no medal at the end of chemo for not having had to take a treatment for a side effect or not having called the doctor. Just pick up the phone and call. That’s how your doctor can do their best by you, and how you can be most successful with your treatment.

Aside from that, staying active is really important. Getting out and walking, even if you’re not exercising per se, but just moving around and not being sedentary is important for circulating the blood. We don’t want you to get a blood clot during chemotherapy because you’re not moving. It helps you expand your lungs, so maybe it can help keep your respiratory tract and heart healthier. Go into chemo as fit as possible, and try to maintain activity and mobility during treatment.

Read the rest of this month’s conversations about chemotherapy for prostate cancer.

Clinical Trial: Free Genetic Testing

Dr. Heather Cheng is an Assistant Professor at the University of Washington and Fred Hutchinson Cancer Research Center, and the Director of the Seattle Cancer Care Alliance Prostate Cancer Genetics Clinic.

Prostatepedia spoke with her about a clinical trial she’s running that looks at inherited genetics of men with metastatic prostate cancer.

What attracted you to medicine?

Dr. Heather Cheng: There are a couple of things I love about medicine and especially oncology. One is getting to know patients, finding out what’s most important to them as people, and using that information to help guide discussions and decisions about their treatment in a way that is true to what is most important to them. These days I guess you call this shared decision-making. That’s the most rewarding part about what I do.

Have you had any patients over the years who have changed how you see your own role or how you view the art of the medicine?

Dr. Cheng: I have a lot of patients who fit those criteria. My interest in this area started when I was a first-year Hematology and Oncology fellow. I was in the clinic and it was when we were at the beginning of this wave of new exciting drugs that prolong survival, such as Zytiga (abiraterone) and Xtandi (enzalutamide).

I met this patient who was 43 years old; he had new, aggressive metastatic prostate cancer. His disease blew through every one of the new drugs. It was extremely humbling and disappointing because we were so excited about these drugs, but they didn’t do much to slow his disease. And it was heartbreaking because he was so young. He had a family history of cancer but not prostate cancer. He had a teenaged son. We had a lot of discussions about the effect of his disease on his son. I wondered if there was something genetic, something that was making his cancer so aggressive. And then, what could this mean for his son? His memory has stuck with me.

When I think about the work and research that I do, it’s not just for the individual patient in front of me. I’m also thinking about how we can improve things and advance the field so things can be better for the next generation. How can we make progress as quickly and with as much positive impact as possible?

I met another patient who had a great effect on me. He had just been diagnosed with high-risk prostate cancer, Gleason 9. He was planning to get radiation. As part of a research study, we offered to sequence the DNA of his cancer because he had an unusual appearance of his cancer– ductal histology. He was kind and generous enough to volunteer and participate. It wasn’t going to affect his treatment, but he agreed to help us learn more.

In his cancer, we found a mutation in the BRCA2 gene, the one that many people may have heard of because of its association with breast and ovarian cancer risk. There was suspicion that the mutation could be inherited, so we brought him back for dedicated genetic testing for inherited cancer risk. And, it turns out he did have an inherited version of that mutated BRCA2 gene. He was the first person in his family to be found to carry the mutated version of BRCA2. Neither he nor his family would have known until later if we had not looked in his tumor.

After this, some of his relatives had genetic counseling and were also tested. The sister who had breast cancer had a recurrence and was found to carry the BRCA2 mutation. This information was important for her because it offers additional treatment opportunities for her cancer that might not have otherwise been considered. His daughter was also found to carry the BRCA2 mutation and after learning of this, had a mammogram and was diagnosed with breast cancer. She’s still curable, so she’s going through treatment, but it is possible that she might not have known until much later otherwise.

The importance of test results can extend to relatives in a way that might help more than one person, not just the person that I see in the clinic, but other members of their family. I do want to be clear that these mutations are not found in most people— even those with cancer—but for the people who have these mutations, it can be life saving information for their family members.

What will you be doing, and what can men expect to happen, during your clinical trial?

Dr. Cheng: You can learn about the study from your doctor, support group, or by visiting our website, http://www.GentlemenStudy.org. There is information about the study. You can consent online, confirm that you have metastatic prostate cancer, and check that you’re interested in genetic testing for cancer risk.

There is a questionnaire that many take about 40 minutes to complete, that asks about your knowledge of genetics, basic health, family history of cancer, and demographic information about where you live.

You can upload supporting information about your diagnosis, or you can check a box saying you’d like help from the research team to gather that information on your behalf. Because there are strict privacy laws around medical records, you need to give permission to our team to get medical information for the study on your behalf.

To be eligible, you must have metastatic prostate cancer and must live in the United States. There’s one other exclusion, which is that if you have some blood disorders such as leukemia, we cannot be sure that the test results are valid.

If you meet criteria, you will be mailed a saliva kit, a medical-grade genetic test through Color Genomics, with instructions on how to provide a saliva sample. Follow the instructions carefully and then mail the kit back. Results are typically available within 4 weeks. You will have access to a genetic counselor following your results, and you are invited to follow up in person to our clinic if you live in the area. If you don’t live near us, we can direct you to resources to find a genetic counselor for in-person visit or by telehealth.

The testing for this study is not recreational testing. It is not the same as Ancestry.com or 23andMe. This is clinical, medically appropriate testing if you have metastatic prostate cancer.

Do you share this information with their doctor, or is it up to them to share the information with their doctor?

Dr. Cheng: We strongly encourage participants to share the results and information with their doctors, but our ethical board does not allow us to do this for participants without their specific consent.

Are there any fees for patients?

Dr. Cheng: There is no fee for the patient.

It sounds similar to the process for the Metastatic Prostate Cancer Project, except I don’t think they share their results.

Dr. Cheng: Yes, it is similar to that project. The difference is that the patient or the participant gets results that apply to them individually. The Metastatic Prostate Cancer Project, which is fantastic and an important and innovative study, is de-identified, and the patient doesn’t get individual-level results back.

Their goal is to amass as much data as they can for research.

Dr. Cheng: Correct, yes.

Are you also cataloging the information that you collect?

Dr. Cheng: Yes.

What will you do with the data that you collect?

Dr. Cheng: We’ll be looking at demographics, the proportion of people who have mutations (pathogenic variants), information about family history, and validated measures of knowledge, distress measures and satisfaction with testing.

If patients consent to re-contact, they will be contacted at the conclusion of the study. If there are other follow-up studies, they can opt to learn about those. There will also be an invitation for those who agree to subsequent studies, like treatment studies or PARP-inhibitor studies, for example.

We’re still learning about certain genes, such as ATM mutations and CHEK2 mutations. As we learn more, we may want to update participants on what the field has learned. There are still many important questions that the field needs to answer, and patient engagement and participation will make this happen more quickly. There will be opportunities for those downstream studies.

How many patients are you looking for, overall?

Dr. Cheng: The plan was for 2,000. We have sent kits out to over 350. We still have room for participation!

Join us to read the issue and learn how to participate in Dr. Cheng’s study.

 

Frontiers In Prostate Cancer Genomics

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 the state of genomics for prostate cancer today.

Not a member? Read the rest of this month’s conversations about prostate cancer genomics + prostate cancer genomics clinical trials.

What would you like prostate cancer patients to know about the state of genomics for prostate cancer today?

Dr. Feng: Genomics is becoming an important reality for patients with prostate cancer. We’ve talked about genomics for years in the context of research and possible advances for patients, but we are now reaching the era when these advances are being used in clinical practice or being assessed in clinical trials.

For patients with metastatic prostate cancer, patients with alterations and mismatch repair genes should be treated with immunotherapy (checkpoint blockade) at some point in the course of their treatment. At some point in their treatment, patients who have alterations in the BRCA1 and BRCA2 genes or other DNA repair genes should also enroll on a trial involving a PARP inhibitor.

There are many other trials testing specific biomarkers for selection for patients. For example, a few years ago, Prof. Johann de Bono presented the results of a study looking at an AKT inhibitor for patients with PTEN deleted prostate cancers. That’s currently being explored in a Phase III trial, and we’re eagerly awaiting the results of that.

In addition, the presence of androgen receptor (AR) splice variants is being used to select patients for studies. These need to be tested out. Some are molecular biomarkers rather than genomic biomarkers. But for patients with metastatic prostate cancer, we can point to definite examples where science is becoming clinical reality.

In the context of patients with localized prostate cancer or non-metastatic prostate cancer, we’re also seeing a number of advances. There are several tissue-based biomarkers that are now covered in various contexts by insurance companies, and they can be ordered as standard-of-care clinically.

In one of my roles, I chair the Genitourinary Cancer Committee for the Clinical Trials group NRG Oncology. A number of our national trials are Phase II and now also Phase III. The trials that we’re developing incorporate these genomic biomarkers for patient stratification or patient selection. When you start to see genomic markers like Decipher incorporated into NRG or PAM50 trials, it means that, sooner or later, these will become standard-of-care, assuming that the trials are positive.

Are there any open and enrolling clinical trials that either focus on prostate cancer genomics or incorporate genomics into their design that you think men reading this may either want to look into or ask their doctors about?

Dr. Feng: Two of the most promising studies are in patients who have had surgery for prostate cancer and now have a PSA recurrence. They are both actively enrolling.

The first trial that I would highlight is NRG-GU006. This study is open at hundreds of hospitals in the United States and Canada; it takes men who have a PSA recurrence after prostatectomy. We go back, we profile the prostate cancer sample from those patients, and we assess a biomarker called the PAM50 classifier, which we helped validate in prostate cancer as predicting response to hormonal therapy. Patients get stratified by this biomarker and are then randomized to standard-of-care, which is radiation alone, or to radiation plus the next-generation antiandrogen Erleada (apalutamide). They get both genomic testing with the PAM50 classifier and randomization, as well as the opportunity to be on Erleada (apalutamide).

Another trial that is actively enrolling is the NRG-GU002 trial, which takes patients who have very aggressive recurrences of their prostate cancer after surgery, and tests them using the genomic classifier Decipher. In the control arm, those with aggressive disease get randomized to radiation and hormone therapy or radiation and hormone therapy plus chemotherapy with Taxotere (docetaxel).

We and other groups have many other trials in development trying to incorporate these biomarkers, but those are the two trials that are open and accruing.

Who are the lead investigators on these two trials?

Dr. Feng: On NRG-GU006, the co-leads are Dr. Daniel Spratt from the University of Michigan and me. On the NRG-GU002 trial, the lead is Dr. Mark Hurwitz from Thomas Jefferson University.

Is there anything else that patients might want to consider?

Dr. Feng: For patients with metastatic disease, there are a number of PARP inhibitor studies in development right now. We’re looking to move PARP inhibitors into earlier and earlier disease spaces in select patients, largely based on the presence of DNA repair alterations.

This study using the Genentech AKT inhibitor is exciting to me. It’s a Phase III study for patients with PTEN alterations. Not all prostate cancers are the same, but we have traditionally put prostate cancer into one disease. But the many different cancers that comprise prostate disease could be genomically selected or stratified.

That is the future, right? Smaller and more precise categories?

Dr. Feng: Yes.

Join Prostatepedia.

Prostate Cancer Genomics

This issue is devoted to the genetics and genomics of prostate cancer, which is one of the most promising and exciting areas of prostate cancer research. Already, this line of investigation is having a major impact. For example, by better defining the genomics of patients entering clinical trials, there can be a marked reduction in the number of patients needed to reach statistical significance. This can potentially reduce the costs of drug development dramatically.

Research into the role of genetics and genomic alterations in the biology and treatment of prostate cancer are still at a much earlier stage than it is for breast cancer. While laboratory studies have discovered a wide range of genes that might act to determine prostate cancer behavior in the clinic, proof that these changes actually determine outcome in the clinic are rather limited. There are even fewer examples where drugs attacking these changes have been FDA-approved for the treatment of prostate cancer.

The PD-1 inhibitor, Keytruda (pembrolizumab) is at present the only example. In 2017, this drug was approved to treat cancers that show mismatch repair or microsatellite instability. These mutations are found in a small proportion of prostate cancer patients.

There are a number of mutations targeted by drugs that are in advanced testing, so this list may expand rapidly. One of the more promising targets is BRCA2. Mutations that alter the function of this gene are known to be involved in breast and ovarian cancer. Cancer cells with these BRCA2 mutations become dependent on the protein, PARP, for their survival and drugs that inhibit PARP can be effective therapy. Studies on patients with advanced prostate cancer show that altered BRCA2 is found in 10-30% of cases. PARP inhibitors have shown significant activity in early clinical trials. Randomized controlled trials needed for FDA-approval are in progress.

Genomic information can also be used to determine how likely prostate cancer is to behave aggressively. This can help identify patients who are likely to do well with active surveillance or to be at low risk for recurrence after an initial attempt at curative treatment.

While genomics promises to revolutionize the treatment of prostate cancer, this revolution requires support from the patient community. The key studies can only be done if patients elect to participate in these trials. For this reason, we made sure to provide you with information on how to become involved in this process.

Not a member? Join us to read more about prostate cancer genomics and prostate cancer genomics clinical trials.

Mr. Tony Crispino: Patient + Research Advocacy

Mr. Tony Crispino found out that he had prostate cancer at age 44. In the years since his treatment, he has become an outspoken prostate cancer advocate. Today, he runs a support group for other patients in Las Vegas, Nevada and is a Patient Advocate at Southwest Oncology Group (SWOG) where he works with leaders in prostate cancer research on cutting-edge clinical trials.

He spoke with Prostatepedia about his own journey as well as ways in which you can get involved in advocacy.

How did you find out that you had prostate cancer?

Mr. Crispino: Like most, I was asymptomatic. I was 44 years old and had no reason to believe that I had cancer. I wasn’t even aware that I had a PSA test taken, and I was unaware of what PSA was. It was by chance that I’d had a diagnostic PSA, which was at 20, and then I found out that I had stage IIIB disease.

Which treatment path did you take?

Mr. Crispino: Being diagnosed in 2006, I had fewer options than patients have today. We didn’t have Zytiga (abiraterone), Xtandi (enzalutamide), or Erleada (apalutamide) then. The path I chose was not considered standard-of-care yet, but eventually, it became that for guys with locally advanced disease. I read papers from Harvard, Stanford, UCSF, UCLA, and more, and I decided that a multimodal approach was reasonable. So radiotherapy, hormonal therapy, and participation in research trials were all reasonable. Today, I would likely be offered Zytiga (abiraterone) [per STAMPEDE], six cycles of Taxotere (docetaxel) [per CHAARTED], or both. But I am fortunate to have a good outcome with what I chose. I have not been treated since 2010, and I have a durable remission.

Has the prostate cancer journey changed you in any way?

Mr. Crispino: A cancer diagnosis is a life changing experience for most. Nearly all who are diagnosed and their families have a new reality. My well-known mantra to others diagnosed is to stay positive. I followed that rule, and once I came to understand my condition, it was time to take that lemon and make lemonade. My negatives are obvious, but my positives outweigh them. I have done well with advanced disease and that helps as there are many who are not as fortunate, and it becomes more difficult for them to stay positive.

I got involved as an advocate, which has been one of the blessings in my life. I have been actively involved in support, mentoring, research, serving on guidelines panels, and lobbying, and I have authored many physician-facing documents. I would have never had those opportunities without that diagnosis, and I would never have dreamed of being a part of them.

How did you first become involved with prostate cancer patient advocacy?

Mr. Crispino: Almost immediately, I was an online surfer like never before trying to regain control of my life. It was through this method that I became educated, a support group leader, and determined to be a part of cancer treatment as more than a patient. But first I had to experience the support I received from all those who paved the way ahead of me.

What do you do with Us TOO and SWOG?

Mr. Crispino: Us TOO is education and support. I am well equipped to help in these areas, and I have run the Las Vegas chapter for over 10 years.

SWOG is a fantastic experience. There are only four such networks in the National Cancer Institute (NCI) group called the National Clinical Trials Network (NCTN). Being included in clinical trial design and evaluation is a very unique experience that very few patient representatives in this area of research get to participate in. SWOG has led me to my membership in societies like ASCO, participation in guidelines panels for ASCO, AUA, SUO, ASTRO, and being elected to the Prostate Task Force for the NCI.

Why do you continue reaching out to other men with prostate cancer?

Mr. Crispino: I have a great deal of experience across the board. It is not only helpful to the diagnosed patient but rewarding to be able to help others. Reaching out to the patient community allows me to help the physician community and vice versa. It is very fulfilling.

Do you have any advice for other men with prostate cancer?

Mr. Crispino: Get educated. I tell all those I mentor that educated decisions are always better than emotional decisions or passing the decision on to your oncologist. Shared decision making requires that you have some knowledge before a decision.

Beware of bias, as there is plenty of it in the patient and physician communities. Beware of conflicts of interest, as there is plenty of it in the physician community. Even with good intentions, biases and conflicts of interests are common.

Do you have any advice for men with prostate cancer who’d like to get involved with advocacy but aren’t sure how to go about it?

Mr. Crispino: Just do it! Many of the positions I hold are elected and have term limits. This means that someone has to grab the baton and move the effort forward when I move on. Being a part of effective advocacy requires many things.

Become educated through peer groups and reading, and by that I mean, listen to all experiences and take notes.

Lose or limit your biases. This is easier said than done. We all think that our decisions are the best and can apply to everyone in the same way. Strong bias might help in the physician and patient communities, but it’s not a good trait in research and guidelines panels. It can be harmful in support and education communities.

Define the area in which you think you can be the best advocate. Being an advocate is a broad role. You can lobby and participate in the political side, which I did but I found it wasn’t my niche. You can be a research advocate, a support advocate, a patient-physician liaison, or even an online poster.

Partake in physician-patient group meetings. Whether it’s attending an ASCO, AUA, ASTRO, or coalition meeting, be there. You will see what it’s about and whether it’s for you. This is not always easy as these types of group meetings can require travel. If you cannot do that, you can still be an effective support advocate in various ways. For example, you could advocate online or by attending support groups meetings.

Not a member? Join us.

NRG Oncology’s Clinical Trials

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

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

Why did you become a doctor?

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

It’s an enormous responsibility.

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

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

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

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

What kinds of trials does NRG oncology run?

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

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

Are the participating institutions limited to within the US?

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

Is it difficult to enroll patients in trials?

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

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

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

Why should patients consider joining the clinical trial?

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

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

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

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

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

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

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

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

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

That’s true.

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

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

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

Join us to learn more information about this trial.

Focal Therapy For Prostate Cancer: A Urologist’s View

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.

Not a member? Join us.

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

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

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

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

Join us.

What is focal therapy?

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

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

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

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

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

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

For which men is focal therapy usually an appropriate choice?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What are some of the other controversies over focal therapy?

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

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

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

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

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

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

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

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

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

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

Not a member? Join us to read the rest of this month’s conversations about focal therapy for prostate cancer.

Focal Therapy

In April, we’re talking about focal therapies.

Dr. Snuffy Myers comments:

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

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

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

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

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

Join us to read this month’s conversations about focal therapy.