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Dr. Alicia Morgans: Putting Chemo Into Perspective

Dr. Alicia Morgans is a medical oncologist at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. She specializes in treating advanced prostate cancer and is particularly interested in addressing treatment side effects.

Prostatepedia spoke with her about chemotherapy for prostate cancer.

Why did you become a doctor?

Dr. Alicia Morgans: I’ve known since junior high school that I wanted to not only become a doctor but an oncologist. I knew I wanted to do something in science that engaged people on a personal level, and I had always admired the way physicians could do that. When visiting my grandmother during summers, I often went to her doctor appointments. I loved trying to understand things on a biologic level, and seeing the way the physicians she had listened and tried to help her. Even when they didn’t have a fix to a problem, they could at least serve as a witness to validate her experience and lend support in any way they were able. Oncology specifically has always been a really challenging puzzle to understand, and the best opportunity to form long-term relationships with patients.

Medicine is an amazing way for individuals to engage at a very deep level, not only with intricate and exciting science but also with really rewarding human interaction. I’m glad I made the decision.

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

Dr. Alicia Morgans: There are always patients who change how we move forward with the practice, art, and science of medicine. As it comes to chemotherapy, in particular, there are a number of men that come to mind who, when offered chemotherapy, said there was no way they could do it.

These statements come probably from their prior experience with family members or loved ones who have had bad experiences with chemotherapy. These are real experiences that certainly need to be acknowledged, but I haven’t met a person who we can’t get through at least one cycle of chemotherapy to see if they truly can’t manage it.

Most everyone can get through chemotherapy for prostate cancer because it’s different than chemotherapy for things like breast cancer or leukemia, where we use many drugs in combination that can be intense. This is typically one chemotherapy drug at a time, unless we’re specifically studying more intense combinations in clinical trials.

Most men do pretty well. There are several men who have been so sick from their cancer that, when I’ve given them chemotherapy, they actually feel a lot better, and that is really rewarding. It’s an experience that I use to guide conversations with patients who are frightened of chemotherapy. Sometimes the people who feel the worst at the start feel much better with chemotherapy.

Because the chemo’s killing their cancer?

Dr. Morgans: Exactly.

That’s a really important point you’re making. Just because, say, your neighbor had chemo for breast cancer and had a terrible time, that doesn’t necessarily mean that you will have a terrible time with chemo for prostate cancer.

Dr. Morgans: Absolutely, and there are a number of men who I’ve taken care of through chemotherapy for prostate cancer, men in their 60s and 70s, who have continued to work. Sometimes, men who are in that phase of their career have a little more flexibility with their job, and they can do half days or relax in the afternoon for a half hour and go back to work. Sometimes these are men with relatively physical jobs, and they’re still able to work, other than the day when they’re actually getting treatment, when they’re not able to be physically at work because they’re getting chemotherapy.

It is different than the treatments that we give to young women with breast cancer or people who are getting treatment in the hospital. This is an outpatient treatment. It typically takes about an hour to an hour-and-a-half to infuse. It’s something that we are sure to monitor very closely because we want to be safe, and we want to support people as they develop symptoms. For the most part, people do much better with this type of chemotherapy than they would expect.

At which points are men likely to encounter chemotherapy for prostate cancer?

Dr. Morgans: There are various points at which men can encounter chemotherapy in their prostate cancer journey. This has changed over the last few years. When men have metastatic disease today, whether that’s hormone sensitive or castrate-resistant, we recommend chemotherapy. As of yet, we do not routinely recommend chemotherapy for men who are having radiation for localized disease or for men with biochemical recurrent disease (though both of those populations have been studied in clinical trials, and there appears to be, at least in some of these patients, potential benefits related to that).

There have also been studies looking at neoadjuvant chemotherapy, which is chemo before prostatectomy. There appears to be a potential benefit to that, particularly in high-risk patient populations. But again, that’s not routinely recommended.

For the most part, men with metastatic disease are more routinely being offered chemotherapy, either in hormone-sensitive metastatic disease in the frontline setting or as one of the treatment options in metastatic castrate-resistant disease.

How is it usually sequenced? Or is there a usual sequence?

Dr. Morgans: There’s not a usual sequence, and every individual who is being treated for advanced prostate cancer is probably aware that we don’t have exact data to say which drug should be first, second, or third. These are conversations between men, their doctors, and their families to choose the treatment option that’s best for them.

For men with brand new prostate cancer that is metastatic from the get-go, or for men who have had prostate cancer treatment in the past and now have recurrent disease that’s metastatic but hasn’t yet been treated, we often recommend chemotherapy, particularly for men who have a high volume or high burden of metastatic disease. In that setting, we use six cycles of chemotherapy, and we can help men live longer and feel better. We have data on both the efficacy for improving survival and on the quality of life that show benefits in that population.

It’s important that we use it in that earliest stage of metastatic disease so that we only have to use six cycles of chemotherapy to get a pretty dramatic benefit whereas, if we use it in the later settings, we may use up to ten cycles of chemotherapy for lesser benefit. That’s a consideration when I’m talking to men with high-volume, hormone-sensitive disease.

In the later stages of disease, if we’ve used androgen receptor or hormonal therapies first, then often we switch to chemotherapy after that hormonal approach because it’s a novel mechanism of action and is expected to be more effective. Rather than continuing to hit on the same androgen receptor pathway, we’re using a different way to approach the cancer and overcome resistance.

What are the side effects of chemo like on its own? What about when you’re sequencing it either before or after hormonal therapy? Is there some sort of synergistic or cumulative effect to the side effects?

Dr. Morgans: Usually, we’re using chemotherapy alone with a gonadotropin-releasing hormone (GnRH) agonist or antagonist therapy. That would include therapies like Lupron (leuprolide), Zoladex (goserelin),

and Firmagon (degarelix), medicines that act to stop the testes from making testosterone. Then we add on Taxotere (docetaxel) chemotherapy when we choose the first chemotherapy for men with prostate cancer. The side effects are generally similar whether you use it earlier or later if you’re using it just in combination with that medicine.

With these injections, the most common side effect is fatigue. The next most common thing is neuropathy, which men would experience as a numbness or tingling in their fingertips or toes that, with repeated exposure, can go up into their hands or feet. It can become a more long-lasting issue, or eventually can lead to permanent numbness, especially as you get higher numbers of cycles. For example, if you use ten cycles in the metastatic castrate-resistant setting versus six cycles in the metastatic hormone-sensitive setting, you’re going to have a higher risk of things like neuropathy.

At any point when we’re using chemotherapy, we expect to cause blood counts to go down. Some men need a blood transfusion of either red cells for anemia or platelets for a low platelet count, though that’s relatively uncommon. What’s more common and possible is that the white count, the infection fighting cells, can go down with each dose of chemotherapy, and that count stays down until the bone marrow starts making more cells. We don’t have a transfusion we can give people to make that improve more quickly. That puts men at risk of what’s potentially a life-threatening infection when their blood counts are down, and the more cycles that they have of chemotherapy the longer it takes for their blood counts to recover. That’s another reason to think about using it when you only have to do six cycles as compared to ten.

As men get older, sometimes the side effect burden can become a little more noticeable to them. If we have the opportunity to use chemotherapy in men in their 50s or 60s as opposed to their 70s, we may see that there are fewer side effects. If they’re having a lot of side effects like loss of appetite and weight-loss, fatigue, and pain related directly to their cancer, the side effects of chemotherapy can actually be reduced fatigue, reduced pain, and improved quality of life between cycles.

Because as we said, it’s killing the cancer?

Dr. Morgans: Yes. There was a clinical trial that reported recently indicating that combined Xtandi (enzalutamide) and Taxotere (docetaxel) in addition to the GnRH agonist or antagonist therapy produced more side effects related to chemotherapy when we piled on an additional androgen receptor-directed therapy with the chemotherapy. Although the trial is done, and we see that people ultimately tolerated that more or less, because there was more toxicity and not a benefit to that triple-therapy approach, we’re not recommending that we do anything more at this point than chemotherapy with a GnRH agonist or antagonist. We’re not using a third androgen receptor-directed type medication in that cocktail, and that’s just to say that the more treatments that you add together, the more toxicity related to chemotherapy.

Is there anything men can do before getting chemo to prevent some of these side effects?

Dr. Morgans: One side effect I didn’t mention is that men can have some hair thinning. Usually, they don’t go completely bald, but they can have some hair thinning and some hair loss. Men can use a cold cap during each cycle of chemotherapy, which can reduce hair loss during chemotherapy.

I’ve had a number of patients whose job requires that they put forth a healthy image. We all want a healthy image, but for some men who work in financial spheres, trying to get people to invest in their companies, or if they work in investing, they have expressed to me that they can’t look sick, they can’t have hair loss.

They’ve used these cold caps and have not lost their hair. It’s impressive and surprising to me how effective the caps were for them.

That is something that they can do to try to reduce hair loss. Cold caps are approved for women with breast cancer who are receiving chemotherapy, and they also seem to work in men. They’re not always covered by insurance, but they can be really effective.

Cold caps were FDA-approved in 2017. You can read the FDA press release here: https:// http://www.fda.gov/news-events/ press-announcements/fda-clears-expanded-use-cooling-cap-reduce-hair-loss-during-chemotherapy.]

Other than that, it’s important that men do their best to stay active. The more active they are before chemotherapy, the better able they’ll be to stay active while they’re getting chemotherapy and to make sure that their bowels are moving as regularly as possible. Some of the medicines that we use for even mild nausea associated with chemotherapy can cause constipation.

Download the issue to read the rest of Dr. Morgans’ comments.


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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.

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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.


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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.

 


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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.

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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.

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Global Access To Xtandi

Ms. Merith Basey is the Executive Director of Universities Allied For Essential Medicines (UAEM) North America, a global network of university students who believe that their universities have an opportunity and a responsibility to improve access to publicly funded medicine developed on their campuses.

Prostatepedia spoke to her about UAEM’s Xtandi (enzalutamide) campaign and how prostate cancer patients can help.

Can you tell us about UAEM’s Xtandi (enzalutamide) campaign?

Ms. Basey: We launched this campaign at the University of California in Los Angeles (UCLA) to urge the university to drop its pursuit of a patent claim in India for the drug Xtandi, which people may know by its generic name, enzalutamide. The drug was developed at UCLA with the support of public grants or funds from the National Institutes of Health (NIH) and the Department of Defense (DoD). Xtandi (enzalutamide) is currently sold in the United States at an eye-watering $130,000 per patient per year and around $30,000 in Canada while at the same time we know it is estimated to cost just a few dollars to produce. Obviously, these prices are out of reach for most.

In India, prostate cancer is among the top ten most commonly diagnosed forms of cancer. And yet UCLA filed a patent claim with the High Court of Delhi on behalf of two massive pharmaceutical giants, Pfizer and Astellas that acquired the rights for the medicine from the university. Our concern is that, if this patent is granted, it will further obstruct the introduction of a more affordable, lower priced generic drug onto the Indian market and it will set a very dangerous precedent for the role of universities in determining patient access. We know the potentially devastating impact that this could have for people living with cancer in India and other countries that import their generics from India as well. In our view, the impact of this case goes far beyond this one drug, one community, one country. This is about standing up for health equity and justice and putting people’s lives over profits.

To give you some further background to this story, while UCLA still currently holds three patents on Xtandi. they initially licensed the drug to Medivation, a biotech based in San Francisco. In 2016, Medivation was acquired by Pfizer and they ended up in an agreement with Astellas, a large Japanese pharmaceutical corporation. In the same year, UCLA then sold its royalty interests on the patents for the drug to Royalty Pharma for a massive $1.14 billion dollars. The Xtandi site application in India was initially rejected by the Indian Patent Office on the grounds that it wasn’t patentable. This was when UCLA filed the patent appeal suit with the High Court of Delhi. At UAEM, we believe universities must be part of the solution not part of the problem to the global challenge of high drug prices. They need to live up to their social missions rather than protecting corporate interests. We know the impact it will have on people who need access to this drug as well as others in many countries around the world.

In response, we’ve been organizing students, and they have been leading a campaign at their university to urge the UC President, Janet Napolitano, to drop the patent claim. Students have spoken up at multiple Board of Regents meetings in San Diego, Los Angeles, and San Francisco. They’ve met with some of the deans, and collected over 3,500 signatures that were delivered to Janet Napolitano. At the most recent campus rally the university even appeared to silence the student voices reducing the opportunities to speak and even putting up barriers outside the building. Disappointingly,

The UC offices have acknowledged that they know the campaign is happening but the overall silence from Janet Napolitano and the Regents has been deafening. The university is publicly funded, and the drug was developed with public research dollars, they should not be fighting a court battle on behalf of private pharmaceutical corporations. This is not the role of the university. We believe that they’re on the forefront to provide access to medication for people regardless of income which is not what they’re doing.

How can someone reading this participate? What can we do?

Ms. Basey: There are several ways to help.

1) If you can, any financial donation to UAEM makes a difference. We’re grassroots, a small and lean organization so any donation goes a long way for our campaigning . Learn more here.

2) We’d love to hear from you at: info@uaem.org You can follow us on most social media!

3) Email President Janet Napolitano–she is the woman with the power within the University of California system to drop the claim–at janet@ucop.edu. Tell her why this drug is so important and why the UC should drop the patent claim and make efforts to ensure publicly funded drugs developed on university campuses should be made affordable and accessible to the public who paid for the research in the first place.

4) We’d also like to hear from people who are affected by prostate cancer who might be interested in writing or being part of the campaign. We’d particularly like to hear from people in California as we’re scaling up our efforts there as well as in India.. Your voices matter. Email us at info@uaem.org

We want to make sure that winning this fight sends a message not only to universities about the importance of living up to their social missions but also to pharmaceutical corporations. They’re making billions of dollars off this drug at the expense of patient lives, and we can urge them to do better.

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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.

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

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

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

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

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What is focal therapy?

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

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

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

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

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

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

For which men is focal therapy usually an appropriate choice?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What are some of the other controversies over focal therapy?

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

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

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

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

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

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

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

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

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

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

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Focal Therapy

In April, we’re talking about focal therapies.

Dr. Snuffy Myers comments:

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

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

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

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

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

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Dr. Daniel George on PSA Recurrence

Dr. Daniel James George is Professor of Medicine and Professor in Surgery at Duke University.

Prostatepedia spoke with him recently about biochemically recurrent prostate cancer.

Have you had any patients whose cases have changed either how you view your own role as a doctor or how you view the art of medicine?

Dr. Daniel George: As we evolve new therapies and indications for treatment, it’s really interesting how that affects our relationships with patients. As an oncologist, my relationships with patients have become more longitudinal. What I mean by that is: people are living longer than ever. I’m beginning to recognize my treatments in the context of not just the short-term endpoint of how to control my patient’s disease in the next few months but in terms of the ramifications for his life and long-term survival. What does it mean in terms of his functional well-being, not simply now, but in a year from now or five to ten years from now?

In many ways, it comforts patients to hear the perspective, that I see them as a long-term survivor, and that I’m thinking about the implications of our treatments in a long-term perspective. That helps the patient invest in his own life and well-being for the long-term, whether that be diet, exercise, sleep, or all these other behavioral interventions that can really impact their quality of life.

You’re basically saying that prostate cancer is becoming more of a chronic disease.

Dr. George: It has been for some patients, and we’re beginning to recognize it more and more for all patients.

We used to think of short-term goals for some of our most advanced cases of prostate cancer—just in terms of disease control or palliation and not worry about the long-term implications of treatment. While on the other end of the spectrum we would have cases where we don’t have to treat the disease at all or maybe treat it minimally in others. Now I’m recognizing prostate cancer as a chronic disease for everybody, and so everybody needs to think of the long-term implications of treatments.

Likewise, we need to think of the implications of our sequential therapies and their cumulative side effects.

Can you define M0 prostate cancer, or biochemically recurrent prostate cancer, for patients?

Dr. George: This is probably confusing because of its name. We refer to prostate cancer in terms of stage. Stage refers to the extent of the disease. The Gleason Score or grade refers to how it looks under the microscope, its aggressiveness. But stage refers to the progression of this disease. Do they have bone metastases? Do they have distant lymph node metastases or other sites of disease? Or is it localized?

We usually use three categories: the T stage, which is the localized tumor, the N stage, which is the lymph node status, and then the M stage, which is the presence of metastases that are distant from the prostate. M0 refers to patients who have no distant metastasis. Think of M0 in terms of patients who are newly diagnosed with prostate cancer.

Recurrent prostate cancer patients are those who’ve had local therapy, surgery, or radiation, and who now have evidence of disease recurrence by PSA. After these treatments, we know that your PSA should be 0 or very low, and it should stay low. If your PSA rises and continues to rise, that’s an indication of disease recurrence. Yet, in many cases, they’re what we call M0 because, when we stage the patient with a bone scan or a CT scan, we can’t see any evidence of cancer. Many of those patients have what we might otherwise refer to as microscopic metastatic disease, disease that’s just below the level of detection. Some of them could have local recurrence or recurrence just within the pelvis and regional nodes that’s not distant. We now know from recent studies that the majority of those patients are going to relapse with distant metastatic disease. In other words, they have distant metastatic disease, but it’s just below the level of detection.

So, this is a bit of a misnomer because we’re treating them with systemic whole-body treatment therapy now because we recognize the risk of distant metastatic disease for the majority of these patients. We’re beginning to use newer imagining techniques, such as PET scans, that could be more sensitive at picking up this microscopic metastatic disease. That shouldn’t deter us from applying the current data to that patient population.

I think of M0 prostate cancer as being low-volume castrate resistant prostate cancer. When we think of it that way, it makes sense that the drugs we’re using work and work even better in that low-volume population. We should use them because M0 is just an early continuation of that metastatic process.

What are these systemic approaches that patients are likely to receive? What are the implications down the line in terms of side effects, and in terms of the longer longitudinal quality of life issues you mentioned earlier?

Dr. George: This is an important aspect of the care for these patients because we have two studies—and a third will soon be reported—that demonstrate a clinical benefit from using what we have broadly termed secondary hormonal therapies, therapies that we add to primary androgen deprivation (ADT) or testosterone suppression.

Patients for whom testosterone suppression has failed can respond to another hormonal intervention later. These are drugs that target the androgen receptor, the protein that testosterone binds to, and inhibits it from signaling. It shuts off what seems to be the most common mechanism for resistance to testicular testosterone suppression. That is an overexpression or overabundance of this receptor, which makes prostate cancer cells sensitive to low levels of residual testosterone in the body.

Xtandi (enzalutamide) and Erleada (apalutamide), in two separate Phase III studies, have demonstrated a clinically significant benefit: a delay in the time to metastasis. The FDA has accepted this as a meaningful endpoint because of the degree of delay. It was associated with about a two-year delay in the time to metastasis in this population.

Patients who were at high risk for developing metastatic disease were in the control arm and developing metastatic disease within about a year of coming on the study for the placebo arm. For the treatment arms, with Xtandi (enzalutamide) or Erleada (apalutamide), we’re seeing a delay of about two additional years. That means three years until the time of metastasis.

The results suggest that we’ve changed the progression of this disease dramatically. In addition, both studies showed a strong trend in favor of the treatment arm for improved overall survival associated with this delay in metastasis. Even though the data may not be as complete because it takes a longer time to report, we’re seeing this correlation in metastasis-free survival, if you will.

Again, I caution the semantics here because these patients do have metastases; they just can’t be seen yet. But the delay in that radiographic appearance of metastasis is associated with an improved survival.

What’s the approach to finding smaller metastases earlier on with the newer imaging techniques? And if they are very small, do you treat them aggressively with radiation, do you continue using the systemic therapies, or do you use a combination?

Dr. George: There is a mix of presentations of patients. When we image with a novel PET-imaging tracer, we’re going to see more than one site of disease in most patients. We’re going to see multiple lymph nodes, multiple bone metastases, or maybe lymph and bone metastases.

For a subset of about 20 percent of patients, we see this disease limited to only lymph node disease or only one or two bone metastases. We refer to this as oligometastatic disease, which we have yet to biologically define. Clinically, we know that it’s associated with a longer survival.

Oligometastatic prostate cancer raises the question of whether or not these patients could be managed with therapy localized to those sites, therapy that does not necessarily expose them to further systemic therapy. We don’t have a lot of data in the castrate-resistant setting, but in the hormone-naïve setting, there are some data that suggest that there can be a delay in the time to initiating subsequent hormonal therapy by doing that.

There’s a study out of Europe, but the median effect was relatively small, just a few months. It’s not clear that this is going to be a meaningful difference for most patients, but it is something that can be discussed.

A lot of those treatment approaches can be done with minimal intervention, external radiation, ablations, or limited surgery. Those will be options. But in the majority of these patients that we do this molecular imaging for, we’re going to find evidence of more than one site of disease or multiple lesions. This suggests that they need a systemic therapy approach.

It’s reasonable to extrapolate this data because we know from the placebo arm of these studies that these patients went on to develop metastases in their bone scan or CT scan within months, 50 percent of them within a year, and many of them in just a few months of their subsequent scan. The likelihood is, if we’d done the molecular imaging at baseline on these patients,we would have seen it. Yet still, in this population, we’re seeing a treatment effect.

We see the treatment effect regardless of what level of PSA doubling time you have. In patients who have a PSA doubling time of just two or three months, we see a dramatic treatment effect. In patients who have a doubling effect of eight or ten months, we still see a dramatic treatment effect in terms of prolongation in the time to metastasis—fewer events in those cases, but still, we see that treatment effect.

The PSA doubling time is an important parameter that we’re using now, in addition to these imaging stats, to determine who we should treat with these drugs and their prognosis.

Isn’t doubling time an indication of the aggressiveness of the disease?

Dr. George: It is. We knew this earlier in disease prior to hormones. PSA doubling time was very prognostic for time to metastasis and overall survival. It’s been less studied in the castrate-resistant setting, when patients have progressed on primary hormonal therapy, but we’re still seeing it there. In fact, the results are really dramatic.

There were some abstracts at the Genitourinary Cancer Symposium (GU ASCO) around this data. There have been reports from these two Phase III studies with Xtandi (enzalutamide) and Erleada (apalutamide) that demonstrate this. We believe there is a strong correlation between a shorter PSA doubling time—a shorter time to bone metastasis—and shorter overall survival.

Just to put these studies into context, the requirements were that PSA doubling times were less than ten months. If doubling time is a year or longer, these are slow-growing cancers. Even though they’re castrate-resistant, these are patients who will live for many years with no metastasis, so it’s reasonable just to observe their disease. For the studies, the median or 50th percentile PSA doubling time was around four months. That’s really short and aggressive.

That’s why we saw that the average time to metastasis was just about a year in the control arms. It’s important to recognize where your patient is in this continuum because it guides whether we should treat him like we did on the study, or if their disease is too slow growing to justify the treatment.

What other considerations are important for patients who fall into this category?

Dr. George: The important thing for patients to know: not to worry. I know that as a physician, it’s easy to say ‘don’t worry about your rising PSA level,’ but as a patient, it is hard to ignore.

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